Rip1k inhibitors

ABSTRACT

Disclosed herein are kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, as well as pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and/or combinations may be used to treat or prevent a kinase-associated disease or condition, particularly a RIP1-associated disease or condition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of U.S.Provisional Application No. 63/004,404, filed on Apr. 2, 2020.

FIELD

The present disclosure concerns compounds and methods of making andusing the compounds, such as for inhibiting receptor-interactingprotein-1 kinase (“RIP1”), and for treating diseases and/or conditionsrelated to RIP1.

BACKGROUND

Receptor-interacting protein-1 kinase (referred to herein as “RIP1”)belongs to the tyrosine kinase-like family and is a serine/threonineprotein kinase involved in innate immune signaling. RIP1 plays a centralrole in regulating cell signaling and its role in programmed cell deathhas been linked to various inflammatory diseases, such as inflammatorybowel disease, psoriasis, and other diseases and/or conditionsassociated with inflammation and/or necroptotic cell death.

SUMMARY

Disclosed herein are compounds according to Formula I

wherein ring B is 5-membered or 6-membered heteroaryl;

X is CH₂ or O;

L is a heteroatom or R^(a), provided that R^(a) is not hydrogen;

Z is C₁₋₁₀aliphatic (such as C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₆cycloalkyl); aryl or heteroaryl, each optionally substituted withone or more R⁵ group;

R¹ is independently for each occurrence —NR^(d)R^(d) wherein the twoR^(d) groups together with the nitrogen bound thereto provide aC₃₋₁₀heterocyclic group; —C≡CH, or a -linker-R⁶ group, wherein thelinker is a divalent C₁₋₁₀aliphatic moiety (such as C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl) or C₁₋₁₀cycloaliphatic moiety, and R⁶ isR^(b), —C(R^(f))₃, or —C(R^(f))═C(R^(f))₂; C₅₋₁₀aromatic, orC₃₋₆heterocyclic, each linker optionally substituted with one or morehalo, R^(a), or both;

R² and R³ independently are R^(a) In some embodiments, R² is hydrogen orC₁₋₁₀aliphatic, such as H or C₁₋₆alkyl, and in certain embodiments, R²is C₁₋₆alkyl, such as CH₃ or CD₃;

R⁴ and R⁵ independently are, for each occurrence, R^(e);

R^(a) is independently for each occurrence hydrogen, C₁₋₁₀aliphatic(such as C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, or C₃₋₆cycloalkyl),C₁₋₁₀haloaliphatic, C₅₋₁₀aromatic, or C₃₋₆heterocyclic;

R^(b) is independently for each occurrence —OH, —SH, —OR^(c), —SR^(c),—NR^(e)R^(e), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), or —C(O)NR^(e)R^(e)

R^(c) is independently for each occurrence C₁₋₁₀alkyl (optionallysubstituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkenyl (optionally substitutedwith 1, 2 or 3 R^(e)), C₂₋₁₀alkynyl (optionally substituted with 1, 2 or3 R^(e)), C₃₋₆cycloalkyl (optionally substituted with 1, 2 or 3 R^(e)),or C₅₋₁₀aromatic (optionally substituted with 1, 2 or 3 R^(e));

R^(d) is C₁₋₉aliphatic optionally substituted with 1, 2, or 3 R^(a),R^(b) and/or R^(e) groups;

R^(e) is independently for each occurrence oxo (═O), —OR^(a), N(R^(a))₂,halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, C₃₋₆cycloalkyl, or twoR^(e) groups join together to provide a C₃₋₁₀heterocyclic group with anitrogen to which the two R^(e) groups are bound;

m is 1 to 4; and

n is 0, 1 or 2.

The foregoing and other objects, features, and advantages of theinvention will become more apparent from the following detaileddescription.

DETAILED DESCRIPTION I. Overview of Terms

The following explanations of terms and methods are provided to betterdescribe the present disclosure and to guide those of ordinary skill inthe art in the practice of the present disclosure. The singular forms“a,” “an,” and “the” refer to one or more than one, unless the contextclearly dictates otherwise. The term “or” refers to a single element ofstated alternative elements or a combination of two or more elements,unless the context clearly indicates otherwise. As used herein,“comprises” means “includes.” Thus, “comprising A or B,” means“including A, B, or A and B,” without excluding additional elements. Allreferences, including patents and patent applications cited herein, areincorporated by reference.

Unless otherwise indicated, all numbers expressing quantities ofcomponents, molecular weights, percentages, temperatures, times, and soforth, as used in the specification or claims are to be understood asbeing modified by the term “about.” Accordingly, unless otherwiseindicated, implicitly or explicitly, the numerical parameters set forthare approximations that may depend on the desired properties soughtand/or limits of detection under standard test conditions/methods. Whendirectly and explicitly distinguishing embodiments from discussed priorart, the embodiment numbers are not approximates unless the word “about”is expressly recited.

Unless explained otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood to one of ordinaryskill in the art to which this disclosure pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, suitable methods andmaterials are described below. The materials, methods, and examples areillustrative only and not intended to be limiting.

As used herein, the term “substituted” refers to all subsequentmodifiers in a term, for example in the term “substitutedarylC₁₋₈alkyl,” substitution may occur on the “C₁₋₈alkyl” portion, the“aryl” portion or both portions of the arylC₁₋₈alkyl group.

“Substituted,” when used to modify a specified group or moiety, meansthat at least one, and perhaps two or more, hydrogen atoms of thespecified group or moiety is independently replaced with the same ordifferent substituent groups as defined below. In a particularembodiment, a group, moiety or substituent may be substituted orunsubstituted, unless expressly defined as either “unsubstituted” or“substituted.” Accordingly, any of the groups specified herein may beunsubstituted or substituted unless the context indicates otherwise or aparticular structural formula precludes substitution. In particularembodiments, a substituent may or may not be expressly defined assubstituted, but is still contemplated to be optionally substituted. Forexample, an “aliphatic” or a “cyclic” moiety may be unsubstituted orsubstituted, but an “unsubstituted aliphatic” or an “unsubstitutedcyclic” is not substituted.

“Substituents” or “substituent groups” for substituting for one or morehydrogen atoms on saturated carbon atoms in the specified group ormoiety can be, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰,—N(R⁸⁰)₂, haloalkyl, perhaloalkyl, —CN, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰, —SO₃⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —P(O)(O⁻)₂(M⁺)₂,—P(O)(O⁻)₂M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)N(R⁸⁰)₂, —C(NR⁷⁰)(R⁸⁰)₂,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰ isC₁₋₁₀aliphatic, heteroaliphatic, or cycloaliphatic, typically,C₁₋₆aliphatic, more typically C₁₋₆alkyl, where R⁶⁰ optionally may besubstituted; each R⁷⁰ is independently for each occurrence hydrogen orR⁶⁰; each R⁸⁰ is independently for each occurrence R⁷⁰ or alternatively,two R⁸⁰groups, taken together with the nitrogen atom to which they arebonded, form a 3- to 7-membered heterocycloaliphatic, which optionallyincludes from 1 to 4 of the same or different additional heteroatomsselected from O, N and S, of which N optionally has R⁷⁰ substitution,such as H or C₁-C₃alkyl substitution; and each M⁺ is a counter ion witha net single positive charge. Each M⁺ is independently for eachoccurrence, for example, an alkali metal ion, such as K⁺, Na⁺, Li⁺; anammonium ion, such as ⁺N(R⁶⁰)₄; a protonated amino acid ion, such as alysine ion, or an arginine ion; or an alkaline metal earth ion, such as[Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5) (a subscript “0.5” means,for example, that one of the counter ions for such divalent alkali earthions can be an ionized form of a compound of the invention and the othera typical counter ion such as chloride, or two ionized compounds canserve as counter ions for such divalent alkali earth ions, or a doublyionized compound can serve as the counter ion for such divalent alkaliearth ions). As specific examples, —N(R⁸⁰)₂ includes —NH₂, —NH-alkyl,—NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl,4N-methyl-piperazin-1-yl, N-morpholinyl and the like. Any two hydrogenatoms on a single carbon also can be replaced with, for example, ═O,═NR⁷⁰, ═N—OR⁷⁰, ═N₂ or ═S.

Substituent groups for replacing hydrogen atoms on unsaturated carbonatoms in groups containing unsaturated carbons are, unless otherwisespecified, —R⁶⁰, halo, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —N(R⁸⁰)₂,perhaloalkyl, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺,—SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —PO₃ ⁻²M²⁺,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)N(R⁸⁰)₂, —OC(O)R⁷⁰,—OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰,—NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂,—NR⁷⁰C(NR⁷⁰)R^(7′) and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺are as previously defined. In an independent embodiment, thesubstituents are not —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, or —S⁻M⁺.

Substituent groups for replacing hydrogen atoms on nitrogen atoms ingroups containing such nitrogen atoms are, unless otherwise specified,—R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —N(R⁸⁰)₂, perhaloalkyl, —CN, —NO,—NO₂, —S(O)₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OS(O)₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰,—PO₃ ²⁻(M⁺)₂, —PO₃ ²⁻M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰,—C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂R⁷⁰, —OC(S)OR⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰,R⁷⁰, R⁸⁰ and M⁺ are as previously defined.

In one embodiment, a group that is substituted has at least onesubstituent up to the number of substituents possible for a particularmoiety, such as 1 substituent, 2 substituents, 3 substituents, or 4substituents.

Additionally, in embodiments where a group or moiety is substituted witha substituted substituent, the nesting of such substituted substituentsis limited to three, thereby preventing the formation of polymers. Thus,in a group or moiety comprising a first group that is a substituent on asecond group that is itself a substituent on a third group, which isattached to the parent structure, the first (outermost) group can onlybe substituted with unsubstituted substituents. For example, in a groupcomprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substitutedwith substituents that are not themselves substituted.

Any group or moiety defined herein can be connected to any other portionof a disclosed structure, such as a parent or core structure, as wouldbe understood by a person of ordinary skill in the art, such as byconsidering valence rules, comparison to exemplary species, and/orconsidering functionality, unless the connectivity of the group ormoiety to the other portion of the structure is expressly stated, or isimplied by context.

“Acyl” refers to the group —C(O)R, where R is H, aliphatic,heteroaliphatic, or aromatic (including both aryl and heteroaryl).Exemplary acyl moieties include, but are not limited to, —C(O)H,—C(O)alkyl, —C(O)C₁-C₆alkyl, —C(O)C₁-C₆haloalkyl, —C(O)cycloalkyl,—C(O)alkenyl, —C(O)cycloalkenyl, —C(O)aryl, —C(O)heteroaryl, or—C(O)heterocyclyl. Specific examples include, —C(O)H, —C(O)Me, —C(O)Et,or —C(O)cyclopropyl.

“Aliphatic” refers to a substantially hydrocarbon-based group or moiety.An aliphatic group or moiety can be acyclic, including alkyl, alkenyl,or alkynyl groups (as well as alkylene, alkenylene, or alkynylenegroups), cyclic versions thereof, such as cycloaliphatic groups ormoieties including cycloalkyl, cycloalkenyl or cycloalkynyl, and furtherincluding straight- and branched-chain arrangements, and all stereo andposition isomers as well. Unless expressly stated otherwise, analiphatic group contains from one to twenty-five carbon atoms (C₁₋₂₅);for example, from one to fifteen (C₁₋₁₅), from one to ten (C₁₋₁₀) fromone to six (C₁₋₆), or from one to four carbon atoms (C₁₋₄) for anacyclic aliphatic group or moiety, or from three to fifteen (C₃₋₁₅) fromthree to ten (C₃₋₁₀), from three to six (C₃₋₆), or from three to four(C₃₋₄) carbon atoms for a cycloaliphatic group or moiety. An aliphaticgroup may be substituted or unsubstituted, unless expressly referred toas an “unsubstituted aliphatic” or a “substituted aliphatic.” Analiphatic group can be substituted with one or more substituents (up totwo substituents for each methylene carbon in an aliphatic chain, or upto one substituent for each carbon of a —C═C— double bond in analiphatic chain, or up to one substituent for a carbon of a terminalmethine group).

“Lower aliphatic” refers to an aliphatic group containing from one toten carbon atoms (C₁₋₁₀), such as from one to six (C₁₋₆), or from one tofour (C₁₋₄) carbon atoms; or from three to ten (C₃₋₁₀), such as fromthree to six (C₃₋₆) carbon atoms for a lower cycloaliphatic group.

“Alkoxy” refers to the group —OR, where R is a substituted orunsubstituted alkyl or a substituted or unsubstituted cycloalkyl group.In certain examples R is a C₁₋₆ alkyl group or a C₃₋₆cycloalkyl group.Methoxy (—OCH₃) and ethoxy (—OCH₂CH₃) are exemplary alkoxy groups. In asubstituted alkoxy, R is substituted alkyl or substituted cycloalkyl,examples of which in the presently disclosed compounds includehaloalkoxy groups, such as —OCF₂H.

“Alkoxyalkyl” refers to the group -alkyl-OR, where R is a substituted orunsubstituted alkyl or a substituted or unsubstituted cycloalkyl group;—CH₂CH₂—O—CH₂CH₃ is an exemplary alkoxyalkyl group.

“Alkyl” refers to a saturated aliphatic hydrocarbyl group having from 1to at least 25 (C₁₋₂₅) carbon atoms, more typically 1 to 10 (C₁₋₁₀)carbon atoms such as 1 to 6 (C₁₋₆) carbon atoms. An alkyl moiety may besubstituted or unsubstituted. This term includes, by way of example,linear and branched hydrocarbyl groups such as methyl (CH₃), ethyl(—CH₂CH₃), n-propyl (—CH₂CH₂CH₃), isopropyl (—CH(CH₃)₂), n-butyl(—CH₂CH₂CH₂CH₃), isobutyl (—CH₂CH₂(CH₃)₂), sec-butyl (—CH(CH₃)(CH₂CH₃),t-butyl (—C(CH₃)₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), and neopentyl(—CH₂C(CH₃)₃).

“Amino” refers to the group —NH₂, —NHR, or —NRR, where each Rindependently is selected from H, aliphatic, heteroaliphatic, aromatic,including both aryl and heteroaryl, or heterocycloaliphatic, or two Rgroups together with the nitrogen attached thereto form a heterocyclicring. Examples of such heterocyclic rings include those wherein two Rgroups together with the nitrogen to which they are attached form a—(CH₂)₂₋₅— ring optionally interrupted by one or two heteroatom groups,such as —O— or —N(R^(g)) such as in the groups

wherein R^(g) is R⁷⁰, —C(O)R⁷⁰, —C(O)OR⁶⁰ or —C(O)N(R⁸⁰)₂.

“Amide” refers to the group —N(R)acyl, wherein R is hydrogen,heteroaliphatic, or aliphatic, such as alkyl, particularly C₁₋₆alkyl.

“Aromatic” refers to a cyclic, conjugated group or moiety of, unlessspecified otherwise, from 5 to 15 ring atoms having a single ring (e.g.,phenyl, pyridinyl, or pyrazolyl) or multiple condensed rings in which atleast one ring is aromatic (e.g., naphthyl, indolyl, orpyrazolopyridinyl), that is at least one ring, and optionally multiplecondensed rings, have a continuous, delocalized π-electron system.Typically, the number of out of plane π-electrons corresponds to theHückel rule (4n+2). The point of attachment to the parent structuretypically is through an aromatic portion of the condensed ring system.For example,

However, in certain examples, context or express disclosure may indicatethat the point of attachment is through a non-aromatic portion of thecondensed ring system. For example,

An aromatic group or moiety may comprise only carbon atoms in the ring,such as in an aryl group or moiety, or it may comprise one or more ringcarbon atoms and one or more ring heteroatoms comprising a lone pair ofelectrons (e.g. S, O, N, P, or Si), such as in a heteroaryl group ormoiety. Unless otherwise stated, an aromatic group may be substituted orunsubstituted.

“Aryl” refers to an aromatic carbocyclic group of, unless specifiedotherwise, from 6 to 15 carbon atoms having a single ring (e.g., phenyl)or multiple condensed rings in which at least one ring is aromatic(e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, and the like). If anyaromatic ring portion contains a heteroatom, the group is heteroaryl andnot aryl. Aryl groups may be, for example, monocyclic, bicyclic,tricyclic or tetracyclic. Unless otherwise stated, an aryl group may besubstituted or unsubstituted.

“Araliphatic” refers to an aryl group attached to the parent via analiphatic moiety. Araliphatic includes aralkyl or arylalkyl groups suchas benzyl and phenylethyl.

“Carboxyl” refers to —CO₂H.

“Carboxamide” refers to —C(O)amino.

“Carboxyl ester” or “carboxy ester” refers to the group —C(O)OR, where Ris aliphatic, heteroaliphatic, or aromatic (including both aryl andheteroaryl).

“Carboxylate” refers to —C(O)O⁻ or salts thereof.

“Cyano” refers to the group —CN.

“Cycloaliphatic” refers to a cyclic aliphatic group having a single ring(e.g., cyclohexyl), or multiple rings, such as in a fused, bridged orspirocyclic system, the ring or at least one of the rings in the systemis aliphatic. Typically, the point of attachment to the parent structureis through an aliphatic portion of the multiple ring system.Cycloaliphatic includes saturated and unsaturated systems, includingcycloalkyl, cycloalkenyl and cycloalkynyl. A cycloaliphatic group maycontain from three to twenty-five carbon atoms; for example, from threeto fifteen, from three to ten, or from three to six carbon atoms. Unlessotherwise stated, a cycloaliphatic group may be substituted orunsubstituted. Exemplary cycloaliphatic groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, or cyclohexenyl.

“Halo,” “halide” or “halogen” refers to fluoro, chloro, bromo or iodo.

“Haloalkyl” refers to an alkyl moiety substituted with one or morehalogens. Exemplary haloalkyl moieties include —CH₂F, —CHF₂ and —CF₃.

“Heteroaliphatic” refers to an aliphatic compound or group having atleast one heteroatom and at least one carbon atom, i.e., at least onecarbon atom from an aliphatic compound or group comprising at least twocarbon atoms, has been replaced with an atom having at least one lonepair of electrons, typically nitrogen, oxygen, phosphorus, silicon, orsulfur. Heteroaliphatic compounds or groups may be substituted orunsubstituted, branched or unbranched, chiral or achiral, and/or acyclicor cyclic, such as a heterocycloaliphatic group.

“Heteroaryl” refers to an aromatic group or moiety having, unlessspecified otherwise, from 5 to 15 ring atoms comprising at least onecarbon atom and at least one heteroatom, such as N, S, O, P, or Si. Aheteroaryl group or moiety may comprise a single ring (e.g., pyridinyl,pyrimidinyl or pyrazolyl) or multiple condensed rings (e.g., indolyl,benzopyrazolyl, or pyrazolopyridinyl). A heteroaryl group may containone or more non-aromatic rings fused to an aromatic moiety and suchheteroaryl groups may be linked to the remainder of the molecule throughan aromatic or non-aromatic ring. Heteroaryl groups or moiety may be,for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unlessotherwise stated, a heteroaryl group or moiety may be substituted orunsubstituted.

“Heterocyclyl,” “heterocyclo” and “heterocycle” refer to both aromaticand non-aromatic ring systems, and more specifically refer to a stablethree- to fifteen-membered ring moiety comprising at least one carbonatom, and typically plural carbon atoms, and at least one, such as fromone to five, heteroatoms. The heteroatom(s) may be nitrogen, phosphorus,oxygen, silicon or sulfur atom(s). The heterocyclyl moiety may be amonocyclic moiety, or may comprise multiple rings, such as in a bicyclicor tricyclic ring system, provided that at least one of the ringscontains a heteroatom. Such a multiple ring moiety can include fused orbridged ring systems as well as spirocyclic systems; and any nitrogen,phosphorus, carbon, silicon or sulfur atoms in the heterocyclyl moietycan be optionally oxidized to various oxidation states. For convenience,nitrogens, particularly, but not exclusively, those defined as annulararomatic nitrogens, are meant to include their corresponding N-oxideform, although not explicitly defined as such in a particular example.Thus, for a compound having, for example, a pyridinyl ring, thecorresponding pyridinyl-N-oxide is included as another compound of theinvention, unless expressly excluded or excluded by context. Inaddition, annular nitrogen atoms can be optionally quaternized.Heterocycle includes heteroaryl moieties, and heteroalicyclyl orheterocycloaliphatic moieties, which are heterocyclyl rings that arepartially or fully saturated. Examples of heterocyclyl groups include,but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane,diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,dioxaphospholanyl, and oxadiazolyl.

“Hydroxyl” refers to the group —OH.

“Nitro” refers to the group —NO₂.

“Phosphate” refers to the group —O—P(O)(OR′)₂, where each —OR′independently is —OH; —O-aliphatic, such as —O-alkyl or —O-cycloalkyl;—O-aromatic, including both —O-aryl and —O-heteroaryl; —O-aralkyl; or—OR′ is —O⁻M⁺, where M⁺ is a counter ion with a single positive charge.Each M⁺ may be an alkali ion, such as K⁺, Na⁺, Li⁺; an ammonium ion,such as ⁺N(R″)₄ where R″ is H, aliphatic, heteroaliphatic, or aromatic(including both aryl and heteroaryl); or an alkaline earth ion, such as[Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5). Phosphonooxyalkyl refers tothe group -alkyl-phosphate, such as, for example, —CH₂OP(O)(OH)₂, or asalt thereof, such as —CH₂OP(O)(O⁻Na⁺)₂, and(((dialkoxyphosphoryl)oxy)alkyl) refers to the dialkyl ester of aphosphonooxyalkyl group, such as, for example, —CH₂OP(O)(O-tert-butyl)₂.

“Phosphonate” refers to the group —P(O)(OR′)₂, where each —OR′independently is —OH; —O-aliphatic such as —O-alkyl or —O-cycloalkyl;—O-aromatic, including both —O-aryl and —O-heteroaryl; or —O-aralkyl; or—OR′ is —O⁻M⁺, and M⁺ is a counter ion with a single positive charge.Each M⁺ is a positively charged counterion and may be, by way ofexample, an alkali metal ion, such as K⁺, Na⁺, Li⁺; an ammonium ion,such as ⁺N(R″)₄ where R″ is H, aliphatic, heteroaliphatic, or aromatic(including both aryl and heteroaryl); or an alkaline earth metal ion,such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5). Phosphonoalkylrefers to the group -alkyl-phosphonate, such as, for example,—CH₂P(O)(OH)₂, or —CH₂P(O)(O⁻Na⁺)₂, and ((dialkoxyphosphoryl)alkyl)refers to the dialkyl ester of a phosphonoalkyl group, such as, forexample, —CH₂P(O)(O-tert-butyl)₂.

“Patient” or “Subject” may refer generally to any living being, but moretypically refers to mammals and other animals, particularly humans. Thusdisclosed methods are applicable to both human therapy and veterinaryapplications.

“Pharmaceutically acceptable excipient” refers to a substance, otherthan the active ingredient, that is included in a composition comprisingthe active ingredient. As used herein, an excipient may be incorporatedwithin particles of a pharmaceutical composition, or it may bephysically mixed with particles of a pharmaceutical composition. Anexcipient can be used, for example, to dilute an active agent and/or tomodify properties of a pharmaceutical composition. Excipients caninclude, but are not limited to, anti-adherents, binders, coatings,enteric coatings, disintegrants, flavorings, sweeteners, colorants,lubricants, glidants, sorbents, preservatives, carriers or vehicles.Excipients may be starches and modified starches, cellulose andcellulose derivatives, saccharides and their derivatives such asdisaccharides, polysaccharides and sugar alcohols, protein, syntheticpolymers, crosslinked polymers, antioxidants, amino acids orpreservatives. Exemplary excipients include, but are not limited to,magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose,starches, hydroxypropyl cellulose, hydroxypropyl methylcellulose,xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP),polyethyleneglycol (PEG), tocopheryl polyethylene glycol 1000 succinate(also known as vitamin E TPGS, or TPGS), carboxy methyl cellulose,dipalmitoyl phosphatidyl choline (DPPC), vitamin A, vitamin E, vitaminC, retinyl palmitate, selenium, cysteine, methionine, citric acid,sodium citrate, methyl paraben, propyl paraben, sugar, silica, talc,magnesium carbonate, sodium starch glycolate, tartrazine, aspartame,benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulphiteor lanolin.

An “adjuvant” is a component that modifies the effect of other agents,typically the active ingredient. Adjuvants are often pharmacologicaland/or immunological agents. An adjuvant may modify the effect of anactive ingredient by increasing an immune response. An adjuvant may alsoact as a stabilizing agent for a formulation. Exemplary adjuvantsinclude, but are not limited to, aluminum hydroxide, alum, aluminumphosphate, killed bacteria, squalene, detergents, cytokines, paraffinoil, and combination adjuvants, such as Freund's complete adjuvant orFreund's incomplete adjuvant.

“Pharmaceutically acceptable carrier” refers to an excipient that is acarrier or vehicle, such as a suspension aid, solubilizing aid, oraerosolization aid. Remington: The Science and Practice of Pharmacy, TheUniversity of the Sciences in Philadelphia, Editor, Lippincott,Williams, & Wilkins, Philadelphia, Pa., 21^(st) Edition (2005),incorporated herein by reference, describes exemplary compositions andformulations suitable for pharmaceutical delivery of one or moretherapeutic compositions and additional pharmaceutical agents.

In general, the nature of the carrier will depend on the particular modeof administration being employed. For instance, parenteral formulationsusually comprise injectable fluids that include pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. In some examples, the pharmaceutically acceptable carrier maybe sterile to be suitable for administration to a subject (for example,by parenteral, intramuscular, or subcutaneous injection). In addition tobiologically-neutral carriers, pharmaceutical compositions to beadministered can contain minor amounts of non-toxic auxiliarysubstances, such as wetting or emulsifying agents, preservatives, and pHbuffering agents and the like, for example sodium acetate or sorbitanmonolaurate.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound that are derived from a variety of organic andinorganic counter ions as will be known to a person of ordinary skill inthe art and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate, and the like. “Pharmaceutically acceptable acidaddition salts” are a subset of “pharmaceutically acceptable salts” thatretain the biological effectiveness of the free bases while formed byacid partners. In particular, the disclosed compounds form salts with avariety of pharmaceutically acceptable acids, including, withoutlimitation, inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like, as well asorganic acids such as amino acids, formic acid, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,benzene sulfonic acid, isethionic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoicacid and the like. “Pharmaceutically acceptable base addition salts” area subset of “pharmaceutically acceptable salts” that are derived frominorganic bases such as sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Exemplary salts are the ammonium, potassium, sodium, calcium, andmagnesium salts. Salts derived from pharmaceutically acceptable organicbases include, but are not limited to, salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, methylglucamine, theobromine,purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine,dicyclohexylamine, choline, and caffeine. (See, for example, S. M.Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19which is incorporated herein by reference.) In particular disclosedembodiments, the compounds may be a formate, trifluoroactate,hydrochloride or sodium salt.

“Effective amount” with respect to a compound or pharmaceuticalcomposition refers to an amount of the compound or pharmaceuticalcomposition sufficient to achieve a particular desired result, such asto inhibit a protein or enzyme. In particular embodiments, an “effectiveamount” is an amount sufficient to inhibit RIP1; to elicit a desiredbiological or medical response in a tissue, system, subject or patient;to treat a specified disorder or disease; to ameliorate or eradicate oneor more of its symptoms; and/or to prevent the occurrence of the diseaseor disorder. The amount of a compound which constitutes an “effectiveamount” may vary depending on the compound, the desired result, thedisease state and its severity, the size, age, and gender of the patientto be treated and the like, as will be understood by a person ofordinary skill in the art.

“Prodrug” refers to compounds that are transformed in vivo to yield abiologically active compound, or a compound more biologically activethan the parent compound. In vivo transformation may occur, for example,by hydrolysis or enzymatic conversion. Common examples of prodrugmoieties include, but are not limited to, ester and amide forms of acompound having an active form bearing a carboxylic acid moiety.Examples of pharmaceutically acceptable esters of the compounds of thisinvention include, but are not limited to, esters of phosphate groupsand carboxylic acids, such as aliphatic esters, particularly alkylesters (for example C₁₋₆alkyl esters). Other prodrug moieties includephosphate esters, such as —CH₂—O—P(O)(OR′)₂ or a salt thereof, whereinR′ is H or C₁₋₆alkyl. Acceptable esters also include cycloalkyl estersand arylalkyl esters such as, but not limited to benzyl. Examples ofpharmaceutically acceptable amides of the compounds of this inventioninclude, but are not limited to, primary amides, and secondary andtertiary alkyl amides (for example with between about one and about sixcarbons). Amides and esters of disclosed exemplary embodiments ofcompounds according to the present invention can be prepared accordingto conventional methods. A thorough discussion of prodrugs is providedin T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of a solute. The solvent can be an organicsolvent, an inorganic solvent, or a mixture of both. Exemplary solventsinclude, but are not limited to, alcohols, such as methanol, ethanol,propanol; amides such as N,N-dialiphatic amides, such asN,N-dimethylformamide; tetrahydrofuran; alkylsulfoxides, such asdimethylsulfoxide; water; and combinations thereof. The compoundsdescribed herein can exist in un-solvated as well as solvated forms whencombined with solvents, pharmaceutically acceptable or not, such aswater, ethanol, and the like. Solvated forms of the presently disclosedcompounds are within the scope of the embodiments disclosed herein.

“Sulfonamide” refers to the group or moiety —SO₂amino, or —N(R)sulfonyl,where R is H, aliphatic, heteroaliphatic, or aromatic (including botharyl and heteroaryl).

“Sulfanyl” refers to the group or —SH, —S-aliphatic, —S-heteroaliphatic,—S-aromatic, (including both-S-aryl and —S-heteroaryl).

“Sulfinyl” refers to the group or moiety —S(O)H, —S(O)aliphatic,—S(O)heteroaliphatic, or —S(O)aromatic (including both —S(O)aryl and—S(O)heteroaryl).

“Sulfonyl” refers to the group: —SO₂H, —SO₂aliphatic,—SO₂heteroaliphatic, —SO₂aromatic (including both —SO₂aryl and—SO₂heteroaryl).

“Treating” or “treatment” as used herein concerns treatment of a diseaseor condition of interest in a patient or subject, particularly a humanhaving the disease or condition of interest, and includes by way ofexample, and without limitation:

(i) preventing the disease or condition from occurring in a patient orsubject, in particular, when such patient or subject is predisposed tothe condition but has not yet been diagnosed as having it;

(ii) inhibiting the disease or condition, for example, arresting orslowing its development;

(iii) relieving the disease or condition, for example, causingdiminution of a symptom or regression of the disease or condition or asymptom thereof; or

(iv) stabilizing the disease or condition.

As used herein, the terms “disease” and “condition” can be usedinterchangeably or can be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been determined) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, where a more or lessspecific set of symptoms have been identified by clinicians.

The above definitions and the following general formulas are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluoro groups). Such impermissible substitutionpatterns are easily recognized by a person having ordinary skill in theart.

A person of ordinary skill in the art will appreciate that compounds mayexhibit the phenomena of tautomerism, conformational isomerism,geometric isomerism, and/or optical isomerism. For example, certaindisclosed compounds can include one or more chiral centers and/or doublebonds and as a consequence can exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers,diasteromers, and mixtures thereof, such as racemic mixtures. As anotherexample, certain disclosed compounds can exist in several tautomericforms, including the enol form, the keto form, and mixtures thereof. Asthe various compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric, or geometricisomeric forms, a person of ordinary skill in the art will appreciatethat the disclosed compounds encompass any tautomeric, conformationalisomeric, optical isomeric, and/or geometric isomeric forms of thecompounds described herein, as well as mixtures of these variousdifferent isomeric forms. Mixtures of different isomeric forms,including mixtures of enantiomers and/or stereoisomers, can be separatedto provide each separate enantiomers and/or stereoisomer usingtechniques known to those of ordinary skill in the art, particularlywith the benefit of the present disclosure. In cases of limitedrotation, e.g. around the amide bond or between two directly attachedrings such as pyridinyl rings, biphenyl groups, and the like,atropisomers are also possible and are also specifically included in thecompounds of the invention.

As is understood by those of skill in the art, hydrogen may be presentin any of three isotopes, namely, protium, deuterium and tritium. Incertain embodiments, any or all hydrogens present in the compound, or ina particular group or moiety within the compound, may be enriched indeuterium or tritium relative to the natural abundance for suchisotopes. Thus, a recitation of alkyl includes compounds that areenriched in deuterium relative to protium. A deuterated alkyl group, mayhave one or more protium atoms replaced by deuterium. For example, ethylrefers to both C₂H₅ or C₂H₅ where from 1 to 5 protium atoms are replacedby deuterium, such as in C₂D_(x)H_(5-x).

II. RIP1-Active Compounds and Pharmaceutical Compositions ComprisingRIP1-Active Compounds

A. Compounds

Disclosed herein are compounds and pharmaceutical compositionscomprising such compounds that are useful for inhibiting RIP1 and/or fortreating diseases and/or conditions associated with RIP1. In someembodiments, the compounds are selective kinase inhibitors. For example,exemplary compounds inhibit RIP1 over RIP2, RIP3, or both RIP2 and RIP3.In some embodiments, a compound of the present disclosure can have astructure satisfying Formula I

A person of ordinary skill in the art will appreciate that the disclosedformulas herein include within their scope all hydrates, solvates,physical forms, stereoisomers, N-oxides, tautomers, and prodrugs of theillustrated compounds.

With reference to Formula I:

ring B is 5-membered or 6-membered heteroaryl;

X is CH₂ or O;

L is a heteroatom or R^(a), provided that R^(a) is not hydrogen;

Z is C₁₋₁₀aliphatic (such as C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₆cycloalkyl); aryl or heteroaryl, each optionally substituted withone or more R⁵ group;

R¹ is independently for each occurrence —NR^(d)R^(d) wherein the twoR^(d) groups together with the nitrogen bound thereto provide aC₃₋₁₀heterocyclic group; —C≡CH, or a -linker-R⁶ group, wherein thelinker is a divalent C₁₋₁₀aliphatic moiety (such as C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl) or C₁₋₁₀cycloaliphatic moiety, and R⁶ isR^(b), —C(R^(f))₃, or —C(R^(f))═C(R^(f))₂; C₅₋₁₀aromatic, orC₃₋₆heterocyclic, each linker optionally substituted with one or morehalo, R^(a), or both;

R² and R³ independently are R^(a) In some embodiments, R² is hydrogen orC₁₋₁₀aliphatic, such as H or C₁₋₆alkyl, and in certain embodiments, R²is C₁₋₆alkyl, such as CH₃ or CD₃;

R⁴ and R⁵ independently are, for each occurrence, R^(e);

R^(a) is independently for each occurrence hydrogen, C₁₋₁₀aliphatic(such as C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, or C₃₋₆cycloalkyl),C₁₋₁₀haloaliphatic, C₅₋₁₀aromatic, or C₃₋₆heterocyclic;

R^(b) is independently for each occurrence —OH, —SH, —OR^(c), —SR^(c),—NR^(e)R^(e), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), or —C(O)NR^(e)R^(e)

R^(c) is independently for each occurrence C₁₋₁₀alkyl (optionallysubstituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkenyl (optionally substitutedwith 1, 2 or 3 R^(e)), C₂₋₁₀alkynyl (optionally substituted with 1, 2 or3 R^(e)), C₃₋₆cycloalkyl (optionally substituted with 1, 2 or 3 R^(e)),or C₅₋₁₀aromatic (optionally substituted with 1, 2 or 3 R^(e));

R^(d) is C₁₋₉aliphatic optionally substituted with 1, 2, or 3 R^(a),R^(b) and/or R^(e) groups;

R^(e) is independently for each occurrence oxo (═O), —OR^(a), N(R^(a))₂,halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, C₃₋₆cycloalkyl, or twoR^(e) groups join together to provide a C₃₋₁₀heterocyclic group with anitrogen to which the two R^(e) groups are bound;

m is 1 to 4; and

n is 0, 1 or 2.

In certain embodiments when R¹ is —NR^(d)R^(d) wherein the two R^(d)groups together with the nitrogen bound thereto provide aC₃₋₁₀heterocyclic group, the C₃₋₁₀heterocyclic group optionally includesone, two or three additional heteroatoms selected from nitrogen andoxygen. In some embodiments, the C₃₋₁₀heterocyclic group is substitutedwith one or more R^(e) groups that join together to provide aC₃₋₁₀heterocyclic group and this C₃₋₁₀heterocyclic, along with the R^(b)group can provide a spirocyclic group or a bridged or unbridged bicyclicgroup.

R¹ can be positioned on any suitable carbon atom(s) of phenyl ring A,such as at the 1, 2, 3, or 4 position, illustrated in Formula I. In someembodiments, one R¹ is R^(a), wherein R^(a) is C₁-C₁₀alkyl (e.g.,methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, ordecyl), and a second R¹ is R^(b), wherein R^(b) is halogen (e.g., Br, F,I, or Cl) or —NR^(d)R^(d) wherein two R^(d) groups together with thenitrogen bound thereto provide a C₄₋₉heterocyclic group. In someembodiments, the C₄₋₉heterocyclic group is substituted with one or moreR^(e) groups and/or has one or more additional heteroatoms in additionto the nitrogen to which both R^(d) groups are bound. Some compoundembodiments comprise at least one R¹ group that is an R^(b) group,wherein R^(b) is —NR^(d)R^(d), wherein (i) each R^(d) independently isR^(a) or R^(e); or (ii) two R^(d) groups together with the nitrogenbound thereto provide a C₄₋₉heterocyclic group. In some embodiments,R^(b) is —NR^(d)R^(d), wherein one R^(d) is R^(a), wherein R^(a) is H,and the other R^(d) is R^(e), wherein R^(e) is C₁₋₆haloalkyl. In someembodiments, the heterocyclic group comprises 1 or 2 heteroatoms(including the nitrogen atom of R^(b)). Certain heterocyclic groupscomprise the nitrogen atom of the R^(b) group and either an oxygen atomor an additional nitrogen atom. The heterocyclic groups in some compoundembodiments are bound to the ring A phenyl ring of Formula I via thenitrogen atom of the R^(b) group. In some embodiments, the heterocyclicgroup is substituted with two R^(e) groups, wherein R^(e) isindependently for each occurrence C₁₋₆haloalkyl (e.g., —CH₂Cl) orC₁₋₆heteroalkyl (e.g., CH₂OH). The heterocyclic groups are 6-membered or7-membered heterocyclic groups. In exemplary embodiments, theheterocyclic group is

wherein each n independently is an integer ranging from 0 to 4, such as0, 1, 2, 3, or 4; and R⁶ is selected from hydrogen; aliphatic, such asC₁₋₁₀aliphatic; aromatic, such as C₅₋₁₀aromatic; or heteroaliphatic,such as C₁₋₁₀heteroaliphatic.

In some embodiments, R¹ is R^(b) wherein R^(b) is —NR^(d)R^(d) and bothR^(d) groups together with the nitrogen bound thereto provide aC₄₋₉heterocyclic group substituted with at least two R^(e) groupswherein the two R^(e) groups join together to provide aC₃₋₁₀heterocyclic group with the R^(b)group to which they are attached.In such embodiments, the two R^(e) groups can join together such that abicyclic group or a spirocyclic group is provided (wherein one ring ofthe bicyclic group or spirocyclic group is provided by the R^(b) groupand the other ring of the bicylic group or the spirocyclic group isprovided by the two R^(e) groups). In embodiments comprising aspirocyclic group, each ring of the spirocyclic group may have the samenumber of atoms or a different number of atoms. In particularembodiments, the spirocyclic group comprises at least two rings, whereina first ring and a second ring of the spirocyclic group have a differentnumber of carbon atoms, a different number of heteroatoms, or both. Insome embodiments, the two rings of the spirocyclic group comprise thesame number of carbon atoms, the same number of heteroatoms, or both. Insome embodiments, each ring of the spirocyclic group comprises aheteroatom in the ring and the heteroatom may be the same in each ring,or each ring of the spirocyclic group may have a different heteroatom inthe ring. The spirocyclic group can comprise a first ring coupled to acarbon atom of the ring A phenyl group, wherein the first ring has from3 to 7 atoms, and a second ring has from 3 to 7 atoms. In someembodiments, the spirocyclic group comprises at least one oxygen atom inaddition to the nitrogen atom of the R^(b) group. The spirocyclic groupmay comprise greater than 7 total atoms in the spirocyclic system withparticular embodiments comprising 9 total atoms in the spirocyclicsystem. In exemplary embodiments, R^(b) together with two R^(e) groupscan provide the following spirocycles:

wherein R⁶ is selected from hydrogen; aliphatic, such as C₁₋₁₀aliphatic;aromatic, such as C₅₋₁₀aromatic; or heteroaliphatic, such asC₁₋₁₀heteroaliphatic.

By way of example of such moieties, in certain embodiments, R¹ isselected from

wherein each n independently is an integer ranging from 0 to 4, such as0, 1, 2, 3, or 4; and R⁶ independently is selected from hydrogen;aliphatic, such as C₁₋₁₀aliphatic; aromatic, such as C₅₋₁₀aromatic; orheteroaliphatic, such as C₁₋₁₀heteroaliphatic.

In certain embodiments, R¹ is a -linker-R⁶ group, such as a C₂₋₁₀alkynylmoiety. Such C₂₋₁₀alkynyl moieties may be linear, branched, and/orcyclic, and have one, two or three substituents. Exemplary substituentsinclude cycloalkyl and OH. In some embodiments, one substituent isoxetanyl, azetidinyl, pyridinyl, pyrrolidinyl, piperidinyl,tetrahydrofuranyl, tetrahydropyranyl, amino, or phosphate, and/or insome embodiments, one substituent is —OC(O)—R⁸. The C₂₋₁₀alkyne maycomprise a linear and/or branched section and a cyclic section, such asin

Some compounds comprise a linker that is a C₁ group and an R⁶ group thatis R^(b), wherein R^(b) is —NR^(d)R^(d) wherein one R^(d) is H and theother R^(d) is pyridinyl, or wherein both R^(d) groups together with thenitrogen bound thereto provide a C₅₋₁₀heteroaryl; or R^(b) is OR^(c),wherein R^(c) is C₁₋₄alkyl substituted with a pyridinyl group. In someembodiments, R^(b) is

In some embodiments, R¹ can be selected from any of the following:

In particular embodiments, R¹ is selected from

In some embodiments, each of R² and R³ independently is R^(a) whereinR^(a) is independently in each occurrence hydrogen, methyl, ethyl,propyl, butyl, pentyl, or hexyl. In particular embodiments, each of R²and R³ independently is R^(a) which is independently for each occurrencehydrogen, methyl, or ethyl. In exemplary embodiments, R² is methyl andR³ is hydrogen.

With reference to each of the embodiments described above, X is CH₂ orO.

In particular embodiments of Formula I, including those described above,the B ring heteroaryl group is five-membered. Such five-memberedheteroaryl groups can have a structure satisfying formula

wherein at least one W is nitrogen, and each remaining W independentlyis selected from C, —C(R^(a))—, CH, oxygen, sulfur, nitrogen, or NH. Insome embodiments, the 5-membered heteroaryl group is a triazole, adiazole, such as an imidazole or a pyrazole, an oxazole or anoxadiazole.

Exemplary diazoles and triazoles include any of the following:

Exemplary oxazoles include any of the following:

In other embodiments, B is six membered heteroaryl, such as a pyridine,pyridazine, pyrimidine or pyrazine.

In certain embodiments, L is a divalent C₁₋₁₀aliphatic group; such as aC₁-C₄alkylene linker (e.g., —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂—). In some embodiments, L is —CH₂—.

With continued reference to Formula I, Z may be aryl, such as phenyl, orheteroaryl. In embodiments where Z is heteroaryl, Z may be a 5-memberedor 6-membered heteroaryl, such as a 5-membered or 6-memberednitrogen-containing heteroaryl, for example, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl, or triazolyl.In certain such embodiments, Z is a 6-membered nitrogen-containingheteroaryl, and may be pyridinyl, pyrimidinyl or pyridazinyl.

In certain embodiments Z is aryl, such as

wherein R⁵ is for each occurrence independently R^(e) and p is 0, 1, 2,3, 4, or 5. In other embodiments Z is heteroaryl, such as

Certain disclosed compounds comprise an R⁵ group that is an R^(a) group,wherein R^(a) is C₁-C₄aliphatic, or that is an R^(b) group, whereinR^(b) is halogen, such as fluoro, R² is R^(a) wherein R^(a) isC₁-C₄aliphatic, and R³ is R^(a), wherein R^(a) is hydrogen.

The compounds of Formulas I can also have structures satisfying any oneor more of Formulas II and IIA-IIF, IIG and IIH.

With reference to Formulas II and IIA-IIH, each of R¹, X, W and R⁵ areas recited above for Formula L In particular embodiments, 0, 1, or 2 R⁵groups are present. R⁵ can be R^(e) wherein R^(e) is fluoro or chloro.In other particular embodiments, R⁵ is not present. With reference toFormulas IIA-F, each W independently is nitrogen or oxygen, andparticularly nitrogen. In particular embodiments Formula E has theformula IIK.

wherein W is O or N. As understood by those of ordinary skill in theart, when W is N in Formula IIK, the N has an open valence and may besubstituted with hydrogen or, with reference to Formula I, an R^(e)group. By way of example, suitable Re groups for substitution of thenitrogen in such instances includes C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆heteroalkyl, C₃₋₆cycloalkyl.

Certain exemplary compounds within the scope of one or more of FormulasI, II, and IIA-IIG, IIH and IIK include:

Compound Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

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In some embodiments, one or more of the compounds can be included in apharmaceutical composition or medicament, and in some embodiments thecompound or compounds can be in the form of the parent compound or apharmaceutically acceptable salt, a stereoisomer, an N-oxide, atautomer, a hydrate, a solvate, an isotope, or a prodrug thereof. Thepharmaceutical composition typically includes at least one additionalcomponent other than a disclosed compound or compounds, such as apharmaceutically acceptable excipient, an adjuvant, an additionaltherapeutic agent (described in the following section), or anycombination thereof.

Pharmaceutically acceptable excipients can be included in pharmaceuticalcompositions for a variety of purposes, such as to dilute apharmaceutical composition for delivery to a subject, to facilitateprocessing of the formulation, to provide advantageous materialproperties to the formulation, to facilitate dispersion from a deliverydevice, to stabilize the formulation (e.g., antioxidants or buffers), toprovide a pleasant or palatable taste or consistency to the formulation,or the like. The pharmaceutically acceptable excipient(s) may include apharmaceutically acceptable carrier(s). Exemplary excipients include,but are not limited to: mono-, di-, and polysaccharides, sugar alcoholsand other polyols, such as, lactose, glucose, raffinose, melezitose,lactitol, maltitol, trehalose, sucrose, mannitol, starch, orcombinations thereof; surfactants, such as sorbitols, diphosphatidylcholine, and lecithin; bulking agents; buffers, such as phosphate andcitrate buffers; anti-adherents, such as magnesium stearate; binders,such as saccharides (including disaccharides, such as sucrose andlactose,), polysaccharides (such as starches, cellulose,microcrystalline cellulose, cellulose ethers (such as hydroxypropylcellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone,polyalkylene glycols); coatings (such as cellulose ethers, includinghydroxypropylmethyl cellulose, shellac, corn protein zein, and gelatin);release aids (such as enteric coatings); disintegrants (such ascrospovidone, crosslinked sodium carboxymethyl cellulose, and sodiumstarch glycolate); fillers (such as dibasic calcium phosphate, vegetablefats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calciumcarbonate, and magnesium stearate); flavors and sweeteners (such asmint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla;lubricants (such as minerals, exemplified by talc or silica, fats,exemplified by vegetable stearin, magnesium stearate or stearic acid);preservatives (such as antioxidants exemplified by vitamin A, vitamin E,vitamin C, retinyl palmitate, and selenium, amino acids, exemplified bycysteine and methionine, citric acid and sodium citrate, parabens,exemplified by methyl paraben and propyl paraben); colorants;compression aids; emulsifying agents; encapsulation agents; gums;granulation agents; and combinations thereof.

III. Methods of Using Compounds

A. Diseases/Disorders

The disclosed compounds, as well as combinations and/or pharmaceuticalcompositions thereof, may be used to inhibit a RIP1 kinase by contactingthe kinase either in vivo or ex vivo, with a compound or compounds ofthe present disclosure, or a composition comprising a compound orcompounds of the present disclosure. Disclosed compound or compounds, orcompositions comprising a disclosed compound or compounds also can beused to ameliorate, treat or prevent a variety of diseases and/ordisorders. In particular embodiments, the disclosed compound,combinations of disclosed compounds, or pharmaceutical compositionsthereof, may be useful for treating conditions in which inhibition ofRIP1 or a pathway involving RIP1 is therapeutically useful. In someembodiments, the compounds directly inhibit RIP1 kinase activity. Incertain embodiments, disclosed compounds are useful for treatingauto-immune diseases, inflammatory disorders, cardiovascular diseases,nerve disorders, neurodegenerative disorders, allergic disorders,respiratory diseases, kidney diseases, cancers, ischemic conditions,erythrocyte deficiencies, lung and brain injuries (e.g., induced byischemia-reperfusion or cisplatin and/or cerebrovascular accident), andbacterial and viral infections.

In some embodiments, the disclosed compound, combinations of disclosedcompounds, or pharmaceutical compositions thereof, may be used to treator prevent allergic diseases, amyotrophic lateral sclerosis (ALS),spinal muscular atrophy, systemic lupus erythematosus, rheumatoidarthritis, type I diabetes mellitus, inflammatory bowel disease, biliarycirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerativecolitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmunemyositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmyopathy,or asthma.

The disclosed compound, combinations of disclosed compounds, orpharmaceutical compositions thereof, may also be useful for treatingimmune regulatory disorders related to bone marrow or organ transplantrejection or graft-versus-host disease. Examples of inflammatory andimmune regulatory disorders that can be treated with the compounds (orpharmaceutical compositions or combinations thereof) include, but arenot limited to, transplantation of organs or tissue, graft-versus-hostdiseases brought about by transplantation, autoimmune syndromesincluding rheumatoid arthritis, systemic lupus erythematosus,Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis,systemic inflammatory response syndrome, myasthenia gravis, type Idiabetes, uveitis, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, postinfectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis, inflammatory andhyperproliferative skin diseases, psoriasis, atopic dermatitis, contactdermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichenplanus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupuserythematosus, acne, alopecia areata, keratoconjunctivitis, vernalconjunctivitis, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical cornea, dystrophia epithelialis corneae,corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves'opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollenallergies, reversible obstructive airway disease, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, bronchitis, gastric ulcers, vascular damage causedby ischemic diseases and thrombosis, ischemic bowel diseases,ischemia-reperfusion injuries, inflammatory bowel diseases, necrotizingenterocolitis, intestinal lesions associated with thermal burns, celiacdiseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn'sdisease, ulcerative colitis, migraine, rhinitis, eczema, interstitialnephritis, Goodpasture's syndrome, hemolytic-uremic syndrome, diabeticnephropathy, multiple myositis, Guillain-Barre syndrome, Meniere'sdisease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis or myocardial infarction, scleroderma (includingsystemic scleroderma), anti-phospholipid syndrome, Wegener's granuloma,Sjögren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, retinaldegeneration, retinal detachment, senile macular degeneration, vitrealscarring, corneal alkali burn, dermatitis erythema multiforme, linearIgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis,sepsis, pancreatitis, diseases caused by environmental pollution, aging,carcinogenesis, metastasis of carcinoma and hypobaropathy, diseasecaused by histamine or leukotriene-C4 release, Behcet's disease,autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis,partial liver resection, acute liver necrosis, necrosis caused by toxin,viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-Bhepatitis, cirrhosis, alcoholic liver disease, including alcoholiccirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis(NASH), autoimmune hepatobiliary diseases, acetaminophen toxicity,hepatotoxicity, hepatic failure, fulminant hepatic failure, late-onsethepatic failure, “acute-on-chronic” liver failure, chronic kidneydiseases, kidney damage/injury (caused by, for example, nephritis, renaltransplant, surgery, administration of nephrotoxic drugs, acute kidneyinjury), augmentation of chemotherapeutic effect, cytomegalovirusinfection, HCMV infection, AIDS, cancer, senile dementia, Parkinson'sdisease, trauma, or chronic bacterial infection.

In certain embodiments the present compounds are useful for treatingnerve pain, including neuropathic pain and inflammation induced pain.

In certain embodiments, the compounds are useful for treatinginterleukin-1 converting enzyme-associated associated fever syndrome,tumor necrosis factor receptor-associated periodic syndrome,NEMO-deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chainassembly complex deficiency syndrome, lysosomal storage diseases (e.g.,Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis,aspartylglucosaminuria, cholesteryl ester storage disease, chronichexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease,Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis,mucolipidosis, infantile free sialic acid storage disease, juvenilehexosaminidase A deficiency, Krabbe disease, lysosomal acid lipasedeficiency, metachromatic leukodystrophy, mucopolysaccharidosesdisorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronalceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease,Schindler disease, sialic acid storage disease, Tay-Sach disease, andWolman disease).

In certain embodiments, the disclosed compound, combinations ofdisclosed compounds, or pharmaceutical compositions thereof, are usefulfor treating and/or preventing rheumatoid arthritis, psoriaticarthritis, osteoarthritis, systemic lupus erythematosus, lupusnephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis,multiple sclerosis, psoriasis, in particular pustular psoriasis, type Idiabetes, type II diabetes, inflammatory bowel disease (Crohn's diseaseand ulcerative colitis), hyperimmunoglobulinemia d and periodic feversyndrome, cryopyrin-associated periodic syndromes, Schnitzler'ssyndrome, systemic juvenile idiopathic arthritis, adult's onset Still'sdisease, gout, gout flares, pseudogout, sapho syndrome, Castleman'sdisease, sepsis, stroke, atherosclerosis, celiac disease, DIRA(deficiency of Il-1 receptor antagonist), Alzheimer's disease,Huntington's disease, or Parkinson's disease.

Proliferative diseases that may be treated by the disclosed compound,combinations of disclosed compounds, or pharmaceutical compositionsthereof, include benign or malignant tumors, solid tumor, carcinoma ofthe brain, kidney, liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin,bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiplemyeloma, gastrointestinal cancer, especially colon carcinoma orcolorectal adenoma, a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, amammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, IL-1 driven disorders, a MyD88driven disorder (such as ABC diffuse large B-cell lymphoma (DLBCL),Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneousT-cell lymphoma or chronic lymphocytic leukemia), smoldering or indolentmultiple myeloma, or hematological malignancies (including leukemia,acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocyticleukemia (CLL), chronic lymphocytic lymphoma, chronic myeloid leukemia(CML), primary effusion lymphoma, Burkitt lymphoma/leukemia, acutelymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma, myelodysplastic/myeloproliferative neoplasms (MDS/MPN) such aschronic myelomonocytic leukemia (CMML, including CMML-0, CMML-1 andCMML-2), myelofibrosis, polycythemia vera, Kaposi's sarcoma,Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma,multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). Inparticular, the presently disclosed compounds are useful in treatingdrug resistant malignancies, such as those resistant to JAK inhibitorsibrutinib resistant malignancies, including ibrutinib resistanthematological malignancies, such as ibrutinib resistant CLL andibrutinib resistant Waldenström's macroglobulinemia.

Despite CMML having certain clinical and pathological features of both amyeloproliferative neoplasm (MPN) and a myelodysplastic syndrome (MDS),CMML is classified by the World Health Organization (WHO) in a separatecategory of an MDS/MPN overlap group. (Arber et al. “The 2016 revisionto the World Health Organization classification of myeloid neoplasms andacute leukemia” Blood, vol. 127, number 20, pages 2391-2405, May 19,2016.) According to the WHO, the diagnosis of CMML now requires both thepresence of persistent peripheral blood monocytosis of ≥1×10⁹/L andmonocytes accounting for ≥10% of the white blood cell (WBC) differentialcount. Additionally, CMML can only be diagnosed per the definition whenrearrangements in PDGFRA, PDGFRB or FGFR1 genes have been excluded, andin the 2016 update, the PCM1-JAK2 fusion gene was added as an excludingcriterion. In some embodiments, a method for treating CMML comprisesidentifying a subject having the WHO diagnosis criteria (i.e.,persistent peripheral blood monocytosis of ≥1×10⁹/L and monocytesaccounting for ≥10% of the white blood cell differential count) andexcluding rearrangements in PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 genes),and treating the subject by administering a RIP1 inhibitor disclosedherein, combinations of such compounds, and/or compositions thereof.

Examples of allergic disorders that may be treated using the disclosedcompound, combinations of disclosed compounds, or pharmaceuticalcompositions thereof, include, but are not limited to, asthma (e.g.atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma,non-atopic asthma, bronchial asthma, non-allergic asthma, essentialasthma, true asthma, intrinsic asthma caused by pathophysiologicdisturbances, essential asthma of unknown or unapparent cause,emphysematous asthma, exercise-induced asthma, emotion-induced asthma,extrinsic asthma caused by environmental factors, cold air inducedasthma, occupational asthma, infective asthma caused by or associatedwith bacterial, fungal, protozoal, or viral infection, incipient asthma,wheezy infant syndrome, bronchiolitis, cough variant asthma ordrug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA),allergic rhinitis, perennial allergic rhinitis, perennial rhinitis,vasomotor rhinitis, post-nasal drip, purulent or non-purulent sinusitis,acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoidsinusitis.

As another example, rheumatoid arthritis (RA) typically results inswelling, pain, loss of motion and tenderness of target jointsthroughout the body. RA is characterized by chronically inflamedsynovium that is densely crowded with lymphocytes. The synovialmembrane, which is typically one cell layer thick, becomes intenselycellular and assumes a form similar to lymphoid tissue, includingdendritic cells, T-, B- and NK cells, macrophages and clusters of plasmacells. This process, as well as a plethora of immunopathologicalmechanisms including the formation of antigen-immunoglobulin complexes,eventually result in destruction of the integrity of the joint,resulting in deformity, permanent loss of function and/or bone erosionat or near the joint. The disclosed compound, combinations of disclosedcompounds, or pharmaceutical compositions thereof, may be used to treat,ameliorate or prevent any one, several or all of these symptoms of RA.Thus, in the context of RA, the compounds are considered to providetherapeutic benefit when a reduction or amelioration of any of thesymptoms commonly associated with RA is achieved, regardless of whetherthe treatment results in a concomitant treatment of the underlying RAand/or a reduction in the amount of circulating rheumatoid factor(“RF”).

The American College of Rheumatology (ACR) has developed criteria fordefining improvement and clinical remission in RA. Once such parameter,the ACR20 (ACR criteria for 20% clinical improvement), requires a 20%improvement in the tender and swollen joint count, as well as a 20%improvement in 3 of the following 5 parameters: patient's globalassessment, physician's global assessment, patient's assessment of pain,degree of disability, and level of acute phase reactant. These criteriahave been expanded for 50% and 70% improvement in ACR50 and ACR70,respectively. Other criteria include Paulu's criteria and radiographicprogression (e.g. Sharp score).

In some embodiments, therapeutic benefit in patients suffering from RAis achieved when the patient exhibits an ACR20. In specific embodiments,ACR improvements of ACRC50 or even ACR70 may be achieved.

B. Combinations of Therapeutic Agents

The compounds described herein may be used alone, in combination withone another, in separate pharmaceutical compositions, together in asingle pharmaceutical composition, or as an adjunct to, or incombination with, other established therapies. The compound or compoundsor composition comprising the compound (or compounds) may beadministered once, or in plural administrations. In some embodiments,the compounds of the present invention may be used in combination withother therapeutic agents useful for the disorder or condition beingtreated. These other therapeutic agents may be administeredsimultaneously, sequentially in any order, by the same route ofadministration, or by a different route as the presently disclosedcompounds. For sequential administration, the compound(s) and thetherapeutic agent(s) may be administered such that an effective timeperiod of at least one compound and the therapeutic agent overlaps withan effective time period of at least one other compound and/ortherapeutic agent. In an exemplary embodiment of a combinationcomprising four components, the effective time period of the firstcomponent administered may overlap with the effective time periods ofthe second, third and fourth components, but the effective time periodsof the second, third and fourth components independently may or may notoverlap with one another. In another exemplary embodiment of acombination comprising four components, the effective time period of thefirst component administered overlaps with the effective time period ofthe second component, but not that of the third or fourth; the effectivetime period of the second component overlaps with those of the first andthird components; and the effective time period of the fourth componentoverlaps with that of the third component only. In some embodiments, theeffective time periods of all compounds and/or therapeutic agentsoverlap with each other.

In some embodiments, the compounds are administered with anothertherapeutic agent, such as an analgesic, an antibiotic, ananticoagulant, an antibody, an anti-inflammatory agent, animmunosuppressant, a guanylate cyclase-C agonist, an intestinalsecretagogue, an antiviral, anticancer, antifungal, or a combinationthereof. The anti-inflammatory agent may be a steroid or a nonsteroidalanti-inflammatory agent. In certain embodiments, the nonsteroidalanti-inflammatory agent is selected from aminosalicylates,cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen,flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin,meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen,oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combinationthereof. In some embodiments, the immunosuppressant is mercaptopurine, acorticosteroid, an alkylating agent, a calcineurin inhibitor, an inosinemonophosphate dehydrogenase inhibitor, antilymphocyte globulin,antithymocyte globulin, an anti-T-cell antibody, or a combinationthereof. In one embodiment, the antibody is infliximab.

In some embodiments, the present compounds may be used with anti-canceror cytotoxic agents. Various classes of anti-cancer and anti-neoplasticcompounds include, but are not limited to, alkylating agents,antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes,antibiotics, enzymes, cytokines, platinum coordination complexes,proteasome inhibitors, substituted ureas, kinase inhibitors, hormonesand hormone antagonists, and hypomethylating agents, for example DNMTinhibitors, such as azacitidine and decitabine. Exemplary alkylatingagents include, without limitation, mechlorothamine, cyclophosphamide,ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines,alkyl sulfonates (e.g., busulfan), and carmustine. Exemplaryantimetabolites include, by way of example and not limitation, folicacid analog methotrexate; pyrmidine analog fluorouracil, cytosinearbinoside; purine analogs mercaptopurine, thioguanine, andazathioprine. Exemplary vinca alkyloids include, by way of example andnot limitation, vinblastine, vincristine, paclitaxel, and colchicine.Exemplary antibiotics include, by way of example and not limitation,actinomycin D, daunorubicin, and bleomycin. An exemplary enzymeeffective as an anti-neoplastic agent includes L-asparaginase. Exemplarycoordination compounds include, by way of example and not limitation,cisplatin and carboplatin. Exemplary hormones and hormone relatedcompounds include, by way of example and not limitation,adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitorsamino glutethimide, formestane, and anastrozole; progestin compoundshydroxyprogesterone caproate, medroxyprogesterone; and anti-estrogencompound tamoxifen.

These and other useful anti-cancer compounds are described in MerckIndex, 13th Ed. (O'Neil M. J. et al., ed.) Merck Publishing Group (2001)and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12thEdition, Brunton L. L. ed., Chapters 60-63, McGraw Hill, (2011), both ofwhich are incorporated by reference herein.

Among the CTLA 4 antibodies that can be used in combination with thepresently disclosed inhibitors is ipilimumab, marketed as YERVOY® byBristol-Myers Squibb.

Other chemotherapeutic agents for combination include immunooncologyagents, such as checkpoint pathway inhibitors, for example, PD-1inhibitors, such as nivolumab and lambrolizumab, and PD-L1 inhibitors,such as pembrolizumab, MEDI-4736 and MPDL3280A/RG7446. Additionalcheckpoint inhibitors for combination with the compounds disclosedherein include, Anti-LAG-3 agents, such as BMS-986016 (MDX-1408).

Further chemotherapeutic agents for combination with the presentlydisclosed inhibitors include Anti-SLAMF7 agents, such as the humanizedmonoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such asthe anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137agents, such as the fully human monoclonal antibody urelumab(BMS-663513).

The presently disclosed compounds also may be used advantageously withCAR-T therapies. Example of currently available CAR-T therapies areaxicabtagene ciloleucel and tisagenlecleucel.

Additional anti-proliferative compounds useful in combination with thecompounds of the present invention include, by way of example and notlimitation, antibodies directed against growth factor receptors (e.g.,anti-Her2); and cytokines such as interferon-α and interferon-γ,interleukin-2, and GM-CSF.

Additional chemotherapeutic agents useful in combination with thepresent compounds include proteasome inhibitors, such as bortezomib,carfilzomib, marizomib and the like.

Examples of kinase inhibitors that are useful in combination with thepresently disclosed compounds, particularly in treating malignanciesinclude: Btk inhibitors, such as ibrutinib; CDK inhibitors, such aspalbociclib; EGFR inhibitors, such as afatinib, erlotinib, gefitinib,lapatinib, osimertinib and vandetinib; Mek inhibitors, such astrametinib; Raf inhibitors, such as dabrafenib, sorafenib andvemurafenib; VEGFR inhibitors, such as axitinib, lenvatinib, nintedanib,pazopanib; BCR-Abl inhibitors, such as bosutinib, dasatinib, imatiniband nilotinib; FLT-3 inhibitors, such as gilteritinib and quizartinib,PI3-kinase inhibitors, such as idelalisib, Syk inhibitors, such asfostamatinib; and JAK inhibitors, such as ruxolitinib and fedratinib.

In other embodiments, the second therapeutic agent may be selected fromany of the following:

analgesics, including morphine, fentanyl, hydromorphone, oxycodone,codeine, acetaminophen, hydrocodone, buprenorphine, tramadol,venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide,dipipanone;

antibiotics, including aminoglycosides (e.g., amikacin, gentamicin,kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems(e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem),cephalosporins (e.g., cefadroxil, cefazolin, cefalotin, cephalexin,cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime,cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, andcefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, andtelavancin), lincosamides (e.g., clindamycin and incomysin),lipopeptides (e.g., daptomycin), macrolides (azithromycin,clarithromycin, dirithromycin, erythromycin, roxithromycin,troleandomycin, telithromycin, and spectinomycin), monobactams (e.g.,aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin),penicilllins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin,cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin,nafcillin, oxacillin, penicillin G, penicillin V, piperacillin,temocillin, and ticarcillin), penicillin combinations (e.g.,amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam,and ticarcillin/clavulanate), polypeptides (e.g., bacitracin, colistin,and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin,gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid,norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, andtemafloxacin), sulfonamides (e.g., mafenide, sulfonamidochrysoidine,sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole,sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole,trimethoprim, and trimethoprim-sulfamethoxaxzole), tetracyclines (e.g.,demeclocycline, doxycycline, minocycline, oxytetracycline, andtetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone,capreomycin, cycloserine, ethambutol, ethionamide, isoniazid,pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, andstreptomycin), and others, such as arsphenamine, chloramphenicol,fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin,platensimycin, quinuprisin/dalfopristin, rifaximin, thiamphenicol,tigecycline, and timidazole;

antibodies—including anti-TNF-α antibodies, e.g., infliximab (Remicade™)adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g.,rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1antibodies, e.g., anakinra; anti PD-1 and/or anti-PD-L1 antibodies, e.g.nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224,MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab,clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab,sarilumab, secukinumab, toralizumab, zanolimumab;

anticoagulants—including warfarin (Coumadin™), acenocoumarol,phenprocoumon, atromentin, phenindione, heparin, fondaparinux,idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin,argatrobam, dabigatran, ximelagatran, batroxobin, hementin;

anti-inflammatory agents—including steroids, e.g., budesonide,nonsteroidal anti-inflammatory agents, e.g., aminosalicylates (e.g.,sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenaseinhibitors (COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac,etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac,ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam,nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac,tolmetin;

immunosuppressants—including mercaptopurine, corticosteroids such asdexamethasone, hydrocortisone, prednisone, methylprednisolone andprednisolone, alkylating agents such as cyclophosphamide, calcineurininhibitors such as cyclosporine, sirolimus and tacrolimus, inhibitors ofinosine monophosphate dehydrogenase (IMPDH) such as mycophenolate,mycophenolate mofetil and azathioprine, and agents designed to suppresscellular immunity while leaving the recipient's humoral immunologicresponse intact, including various antibodies (for example,antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonalanti-T-cell antibodies (OKT3)) and irradiation. Azathioprine iscurrently available from Salix Pharmaceuticals, Inc. under the brandname Azasan; mercaptopurine is currently available from GatePharmaceuticals, Inc. under the brand name Purinethol; prednisone andprednisolone are currently available from Roxane Laboratories, Inc.;Methyl prednisolone is currently available from Pfizer; sirolimus(rapamycin) is currently available from Wyeth-Ayerst under the brandname Rapamune; tacrolimus is currently available from Fujisawa under thebrand name Prograf; cyclosporine is current available from Novartisunder the brand name Sandimmune and Abbott under the brand name Gengraf;IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid arecurrently available from Roche under the brand name Cellcept andNovartis under the brand name Myfortic; azathioprine is currentlyavailable from Glaxo Smith Kline under the brand name Imuran; andantibodies are currently available from Ortho Biotech under the brandname Orthoclone, Novartis under the brand name Simulect (basiliximab)and Roche under the brand name Zenapax (daclizumab); and

Guanylate cyclase-C receptor agonists or intestinal secretagogues, forexample linaclotide, sold under the name Linzess.

These various agents can be used in accordance with their standard orcommon dosages, as specified in the prescribing information accompanyingcommercially available forms of the drugs (see also, the prescribinginformation in the 2006 Edition of The Physician's Desk Reference), thedisclosures of which are incorporated herein by reference.

IV. Methods of Making Compounds

The compounds can be prepared by any suitable method as will beunderstood by a person of ordinary skill in the art. One exemplarysuitable method is provided below with reference to specific compoundsin the examples, and can include the following first reaction stepaccording to Scheme 1.

With reference to Scheme 1, protected amine precursor 100 can be coupledwith R¹ group 102, which comprises an “R⁶-linker” group as illustratedin Scheme 1, using a metal-mediated, cross-coupling reaction to providethe cross-coupled product 104. In some embodiments, the metal-mediated,cross-coupling reaction can be carried out using a transition metalcatalyst, such as a palladium catalyst. Exemplary palladium catalystsinclude, but are not limited to, Pd(0) catalysts (e.g., Pd₂(dba)₃,Pd(dba)₂, Pd(PPh₃)₄, and the like) or Pd(II) catalyst (e.g., XPhos Pdgeneration 2 or generation 3, PdCl₂, Pd(OAc)₂, and the like). In someembodiments, the palladium catalyst can be used in combination withanother co-catalyst, such as CuI, to promote the cross-couplingreaction, such as in a Sonogoshira reaction. The metal-mediated,cross-coupling also can comprise using a base, such as an amine base(e.g., Et₃N), or an inorganic base (e.g., Cs₂CO₃, Na₂CO₃, K₂CO₃ or thelike), and a solvent (e.g., dimethylformamide). With reference to Scheme1, X is a suitable group for metal-mediated, cross-coupling, such as ahalogen or a triflate group and PG is an amine protecting group, whichcan be selected from, but is not limited to, a9-fluorenylmethoxycarbonyl (“Fmoc”) group, a t-butyloxycarbonyl (“Boc”)group, a trityl (“Tr”) group, an allyloxycarbonyl (“Alloc”) group, abenzyloxycarbonyl (“Cbz”) group, and the like.

Synthesis of tert-Butyl(S)-(9-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate8 and tert-Butyl(S)-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate9

Intermediates 8 and 9 are referred to as intermediates II and I,respectively in other schemes herein.

Synthesis of N-(tert-Butoxycarbonyl)-O-(2-nitropyridin-3-yl)-L-serine(3)

To a solution of (tert-butoxycarbonyl)-L-serine 2 (5.13 g, 25.0 mmol) inanhydrous DMF (100 mL) at 0° C. was added sodium hydride (2.0 g, 60% inoil, 50 mmol). The resulting solution was stirred at this temperaturefor 2 hrs, then 3-fluoro-2-nitropyridine 1 (3.60 g, 25.3 mmol) wasadded. The resulting solution was allowed to warm up to ambienttemperature over 8 hrs and quenched with aqueous HCl solution (3N, 25mL) slowly until pH of the solution was around 4. The reaction solutionwas extracted with ethyl acetate (3×120 mL) and the combined organiclayer was washed with brine (40 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. Residueobtained was purified by silica gel chromatography using a gradient of 0to 10% methanol in dichloromethane to affordN-(tert-butoxycarbonyl)-O-(2-nitropyridin-3-yl)-L-serine 3 (5.35 g, 65%)as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.18-8.08 (m, 1H),7.57 (d, J=3.3 Hz, 2H), 5.60 (d, J=7.9 Hz, 1H), 4.76 (d, J=7.8 Hz, 1H),4.64 (dd, J=9.3, 2.9 Hz, 1H), 4.46 (dd, J=9.3, 3.1 Hz, 1H), 1.46 (s,9H). MS (ESI, m/e) Calculated 327.1066; Found 228.1 [M-Boc+H]⁺.

Synthesis of O-(2-Aminopyridin-3-yl)-N-(tert-butoxycarbonyl)-L-serine(4)

To a solution ofN-(tert-butoxycarbonyl)-O-(2-nitropyridin-3-yl)-L-serine 3 (4.81 g,14.72 mmol) in methanol (100 mL) was added 5% palladium on carbon (950mg). The resulting solution was hydrogenated in Parr-Shaker under 60 PSIfor 16 hrs, filtered through Celite and washed with methanol. Thefiltrate was concentrated under reduced pressure to afford crude productO-(2-aminopyridin-3-yl)-N-(tert-butoxycarbonyl)-L-serine 4 (4.40 g, >95%yield) as a pale, yellow solid which was directly used in next stepwithout purification. MS (ESI, m/e) Calculated 297.1325; Found 298.0[M+H]⁺.

Synthesis of tert-Butyl(S)-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate(5)

To a solution of crudeO-(2-aminopyridin-3-yl)-N-(tert-butoxycarbonyl)-L-serine 4 (4.40 g,14.72 mmol) in anhydrous DMF (300 mL) was added diisopropylethylamine(2.09 g, 2.80 mL, 16.19 mmol) followed by HATU (6.16 g, 16.19 mmol). Theresulting solution was stirred at ambient temperature for 2 days, water(200 mL) was then added, and the aqueous solution was extracted withethyl acetate (4×200 mL). Combined organic layer was dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The residue obtained was purified by silica gel chromatographya gradient of using 0 to 5% methanol in dichloromethane to affordtert-butyl(S)-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 5(899 mg, 22% over 2 steps) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.86 (s, 1H), 8.16 (dd, J=4.7, 1.5 Hz, 1H), 7.42 (dd, J=8.0, 1.5 Hz,1H), 7.08 (dd, J=8.0, 4.7 Hz, 1H), 5.64 (s, 1H), 4.73-4.47 (m, 2H), 4.17(dd, J=10.7, 9.4 Hz, 1H), 1.46 (s, 9H). MS (ESI, m/e) Calculated279.1219; Found 280.1 [M+H]⁺.

Synthesis of tert-Butyl(S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate(6)

To a solution of tert-butyl(S)-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl) carbamate5 (796 mg, 2.85 mmol) in anhydrous DMF (28 mL) was added anhydrouscesium carbonate (930 mg, 2.85 mmol) followed by methyl iodide (368 mg,162 μL, 2.59 mmol). The resulting solution was stirred at ambienttemperature for 2 days, followed by addition of water (100 mL) and ethylacetate (100 mL). The organic layer was separated, and the aqueous layerwas extracted with ethyl acetate (2×50 mL). The combined organic layerwas then washed with brine (50 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure to obtain aresidue in DMF solution (about 12 mL). Crude product was purified byreverse HPLC using a gradient of 0 to 50% acetonitrile in water bufferedwith 0.1% formic acid. The desired fractions were combined, basifiedwith saturated sodium bicarbonate aqueous solution and extracted withethyl acetate. The combined organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated under the reduced pressureto afford tert-butyl(S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate6 (434 mg, 57%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (dd,J=4.8, 1.6 Hz, 1H), 7.47 (dd, J=7.9, 1.6 Hz, 1H), 7.14 (dd, J=7.9, 4.7Hz, 1H), 5.59 (d, J=5.2 Hz, 1H), 4.73-4.53 (m, 2H), 4.31-4.12 (m, 1H),3.51 (s, 3H), 1.41 (s, 9H). MS (ESI, m/e) Calculated 293.1376; Found194.1 [M-Boc+H]⁺.

Synthesis of(S)-3-((tert-Butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepine6-oxide (7)

To a solution of tert-butyl(S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate6 (429 mg, 1.46 mmol) in anhydrous dichloromethane (5 mL) was addedmCPBA (730 mg, 77% max purity, 2.93 mmol). The resulting solution wasstirred at ambient temperature for 20 hrs, diluted with dichloromethane(200 mL) and washed with saturated sodium carbonate aqueous solution (20mL) and saturated sodium thiosulfate solution (20 mL). Resulting organiclayer was separated, washed with brine (2×30 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure.Residue obtained was purified by silica gel chromatography using agradient of 0 to 5% methanol in dichloromethane to afford(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine6-oxide 7 (303 mg, 67%). MS (ESI, m/e) Calculated 309.1325; Found 310.0[M+H]⁺. Starting material tert-butyl(S)-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate6 (139 mg, 32%) was partially recovered.

Synthesis of tert-Butyl(S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate(8) and tert-butyl(S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate(9)

To a solution of(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine6-oxide 7 (303 mg, 0.98 mmol) in anhydrous 1,2-dichloroethane (20 mL)was added 4 Å molecular sieves (303 mg) followed by n-tetrabutylammoniumbromide (474 mg, 1.47 mmol). The reaction solution was allowed to stirat ambient temperature for 10 minutes, then 4-methylbenzenesulfonicanhydride (480 mg, 1.47 mmol) was added. The resulting reaction mixturewas then allowed to stir at ambient temperature for 17 hrs and heated at65° C. for 8 hrs, cooled down to ambient temperature, filtered throughCelite and washed with dichloromethane (about 100 mL). The filtrate wasthen washed with saturated sodium bicarbonate aqueous solution, brine,dried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue obtained was purified by silica gelchromatography using a gradient of 0 to 10% methanol in dichloromethaneto afford less polar isomer of tert-butyl(S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate9 (67 mg, 18%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (d,J=8.2 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.30 (d, J=7.0 Hz, 1H), 4.50-4.21(m, 3H), 3.27 (s, 3H), 1.33 (s, 9H). MS (ESI, m/e) Calculated 371.0481;Found 372.0 [M+H]⁺. Additional impure fractions were combined andfurther purified by reverse HPLC using a gradient of 35 to 80%acetonitrile in water buffered with 0.1% formic acid. The desiredfractions were combined and lyophilized to afford the more polar isomerof tert-butyl(S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 8 (85 mg, 23%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.19 (d, J=5.2 Hz, 1H), 7.63 (d, J=5.2 Hz, 1H), 7.38-7.27 (m, 1H),4.51-4.32 (m, 3H), 3.32 (s, 3H), 1.35 (s, 9H). MS (ESI, m/e) Calculated371.0481; Found 372.0 [M+H]⁺. Also starting material(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine6-oxide 7 (61 mg, 20%) was partially recovered.

Synthesis of(S)—N-(5-Methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide14

Synthesis of tert-Butyl(S)-(5-Methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate11

To a solution of(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine6-oxide 7 (24.5 mg, 0.079 mmol) and 8-oxa-2-azaspiro[4.5]decane 10 (14.6mg, 0.103 mmol) in anhydrous dichloroethane (1 mL) was addeddiisopropylethylamine (41 mg, 55 μL, 0.317 mmol) followed by PyBrOP (48mg, 0.103 mmol). The resulting solution was stirred at ambienttemperature for 19 hrs, then heated at 60° C. for 2 days. All solventswere removed under reduced pressure and the residue obtained waspurified by reverse HPLC using a gradient of 0 to 80% acetonitrile inwater buffered with 0.1% formic acid. The desired fractions werecombined, diluted with ethyl acetate and the solution was washed withsaturated sodium bicarbonate aqueous solution, brine, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to afford tert-butyl(S)-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate11 (2.8 mg, 8%). MS (ESI, m/e) Calculated 432.2373; Found 433.2 [M+H]⁺.

Synthesis of(S)-3-Amino-5-methyl-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3-dihydro-pyrido[3,2-b][1,4]oxazepin-4(5H)-oneHydrochloride 12

Hydrogen chloride solution (0.5 mL, 4.0M in dioxane, 2 mmol) was addedto a vial containing tert-butyl(S)-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate11 (2.8 mg) and the resulting solution was stirred at ambienttemperature for 16 hrs. The reaction mixture was then concentrated underreduced pressure to afford crude product(S)-3-amino-5-methyl-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride 12 (2.4 mg, >95% yield) which was used directly in nextstep. MS (ESI, m/e) Calculated 332.1848; Found 333.1 [M+H]⁺.

Synthesis of(S)—N-(5-Methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide14

To a solution of(S)-3-amino-5-methyl-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3-dihydro-pyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride 12 (2.4 mg, 6.48 μmol) and 4-phenoxypicolinic acid 13 (2.8mg, 13 μmol) in anhydrous DMF (0.5 mL) was added diisopropylethylamine(4.2 mg, 5.6 μL, 32 μmol) followed by HATU (4.9 mg, 13 μmol). Theresulting solution was stirred at ambient temperature for 16 hrs. A dropof water was added to quench the reaction and the resulting solution wasdirectly purified by reverse HPLC using a gradient of 40 to 100%acetonitrile in water buffered with 0.1% formic acid. Desired fractionswere combined and diluted with ethyl acetate (60 mL). The solution waswashed with saturated sodium bicarbonate aqueous solution, brine, driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure to afford(S)—N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide14 (2.2 mg, 64%) as a white solid. MS (ESI, m/e) Calculated 529.2325;Found 530.2 [M+H]⁺.

Synthesis of(S)—N-(5-Methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide18

Synthesis of tert-Butyl(S)-(5-Methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate16

To a solution of tert-butyl(S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate9 (32 mg, 85 μmol), Pd₂(dba)₃ (7.8 mg, 8.5 μmol), xantphos (4.9 mg, 8.5μmol) and cesium carbonate (56 mg, 170 μmol) in anhydrous 1,4-dioxane (1mL) was added 7-oxa-2-azaspiro[3.5]nonane (13 mg, 102 μmol). Thereaction solution was purged with nitrogen for 1 minute, sealed andheated at 90° C. for 16 hrs. The reaction solution was cooled to ambienttemperature and diluted with ethyl acetate (50 mL). The resultingsolution was washed with water, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The residueobtained was purified by reverse HPLC using a gradient of 30 to 80%acetonitrile in water buffered with 0.1% formic acid. The desiredfractions were combined, diluted with ethyl acetate (100 mL) and washedsaturated sodium bicarbonate aqueous solution, brine, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to afford tert-butyl(S)-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate16 (35 mg, >95% yield) as a pale liquid. MS (ESI, m/e) Calculated418.2216; Found 419.2 [M+H]⁺.

Synthesis of(S)-3-Amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydro-pyrido[3,2-b][1,4]oxazepin-4(5H)-oneHydrochloride 17

Hydrogen chloride solution (0.5 mL, 4M in dioxane, 2 mmol) was added toa vial containing tert-butyl(S)-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate16 (35 mg, 0.085 mmol) and the reaction mixture was allowed to stir atambient temperature for 16 hrs. All solvents were removed under reducedpressure to afford 1:1 mixture of azetidine ring-opening side productand the desired product(S)-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride 17 which was used directly in next step withoutpurification. MS (ESI, m/e) Calculated 318.1692; Found 319.1 [M+H]⁺.

Synthesis of(S)—N-(5-Methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide18

Crude product(S)-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydropyrido-[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride 17 and 4-phenoxypicolinic acid 13 (27.5 mg, 0.128 mmol)were dissolved in anhydrous DMF (1 mL), and diisopropylethylamine (55mg, 74 μL, 0.425 mmol) was added followed by HATU (48.5 mg, 0.128 mmol).The resulting solution was stirred at ambient temperature for 16 hrs.Two drops of water were added to quench the reaction, and the resultingsolution was directly purified by reverse HPLC using a gradient of 40 to80% acetonitrile in water buffered with 0.1% formic acid. Desiredfractions were combined, diluted with ethyl acetate (60 mL) and theresulting organic solution was washed with saturated sodium bicarbonateaqueous solution (5 mL), brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. Product obtained wasdissolved in 80% acetonitrile in water and lyophilized to afford(S)—N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro-[3.5]nonan-2-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide18 (5.7 mg, 13% over 2 steps). MS (ESI, m/e) Calculated 515.2169; Found516.1 [M+H]⁺.

General Procedure to Prepare 9-Substituted Pyridooxaazepine Compounds

Exemplary 9-substituted pyridooxaazepine compounds were preparedaccording to the general procedure set forth above. Versatileintermediate II can be coupled with a variety of groups, viametal-catalyzed (for example palladium-catalyzed) cross couplingreactions as is known to those of skill in the art. In particularalkynyl groups can be readily coupled to the pyridooxezepine ringaccording to this general scheme by adapting the procedures set forthbelow. By way of example, compounds I-14, I-15 and I-16 were synthesizedby this method.

Step 1: Synthesis of Intermediate (III)

Intermediate II (0.1 mmol, 1 eq), substituted ethyne (0.2 to 0.3 mmol, 2to 3 eq), Pd(PPh₃)₄(0.01 mmol, 0.1 eq) and CuI (0.01 mmol, 0.1 eq) inanhydrous DMF (1 mL) in a vial was added Et₃N (0.4 mmol, 4 eq). Thereaction solution was purged with nitrogen for 1 minute, then sealed andheated at 70° C. for 14 to 24 hours. Reaction solution was cooled toambient temperature, diluted with ethyl acetate (100 mL), washed withbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under the reduced pressure. Residue obtained was purifiedby silica gel chromatography or reverse HPLC (mobile phase A: water with0.1% HCOOH; mobile phase B: acetonitrile with 0.1% HCOOH) to affordintermediate III.

Step 2: Synthesis of Intermediate (IV)

Intermediate III (1 eq) was dissolved in dichloromethane, then TFA(concentration: 10% in dichloromethane) or HCl (40 eq, 4N in dioxane)was added. The resulting solution was stirred at ambient temperatureuntil all starting material disappeared (monitored by reverse HPLC). Allsolvents were removed under the reduced pressure to afford crude productof intermediate IV which was directly used in next step.

Step 3: Synthesis of Final Product (V)

Intermediate IV (1 eq), corresponding acid (1.2 eq), anddiisopropylethylamine (5 eq) were dissolved in DMF (concentration 0.05Mto 0.1M), then HATU (1.2 eq) was added. The resulting solution wasstirred at ambient temperature for 14 to 24 hours. Reaction solution wasadded brine and ethyl acetate. Organic layer was separated and driedover anhydrous magnesium sulfate, filtered, and concentrated under thereduced pressure. Residue obtained was purified by silica gelchromatography or reverse HPLC (mobile phase A: water with 0.1% HCOOH;mobile phase B: acetonitrile with 0.1% HCOOH) to afford final product(V).

Synthesis of(S)—N-(9-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide21

Synthesis of(S)-3-Amino-9-bromo-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-oneHydrochloride 20

Hydrogen chloride solution (1 mL, 4M in dioxane, 4 mmol) was added to avial containing tert-butyl(S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate 8 (52 mg, 0.139 mmol). The resulting solution was stirred atambient temperature for 19 hrs. All solvents were removed under reducedpressure to afford(S)-3-amino-9-bromo-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride 20 (43 mg, 100%) as a white solid. MS (ESI, m/e)Calculated 270.9956; Found 272.0 [M+H]⁺.

(S)—N-(9-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide21

To a solution of(S)-3-amino-9-bromo-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride 20 (43 mg, 85.8 μmol) and 4-phenoxypicolinic acid 13 (45mg, 0.209 mmol) in anhydrous DMF (1.4 mL) was addeddiisopropylethylamine (135.2 mg, 0.18 mL, 1.05 mmol) followed by HATU(79.5 mg, 0.209 mmol). The resulting solution was stirred at ambienttemperature for 16 hrs. Water (0.1 mL) was then added, and the solutionwas directly purified by reverse HPLC using a gradient of 37 to 90%acetonitrile in water buffered with 0.1% formic acid. The desiredfractions were combined, diluted with ethyl acetate (100 mL) and theresulting solution was washed with saturated sodium bicarbonatesolution, brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure to afford(S)—N-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide21 (50 mg, 77%) as a white solid. MS (ESI, m/e) Calculated 468.0433;Found 469.0 [M+H]⁺.

Synthesis of(S)—N-(9-((3-Hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide23 (I-15)

To a solution of(S)—N-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide21 (25 mg, 53 μmol), 3-ethynyloxetan-3-ol 22 (15.7 mg, 0.160 mmol), CuI(1 mg, 5.3 μmol) and Pd(PPh₃)₄ (6.2 mg, 5.3 μmol) in anhydrous DMF (1mL) was added triethylamine (32.4 mg, 45 μL, 0.320 mmol). The reactionsolution was purged with nitrogen for 1 minute, then sealed and heatedat 70° C. for 16 hrs, cooled down to ambient temperature and dilutedwith ethyl acetate (60 mL). The diluted reaction mixture was then washedwith brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby reverse phase HPLC using a gradient of 27 to 67% acetonitrile inwater buffered with 0.1% formic acid. The desired fractions werecombined and lyophilized to afford(S)—N-(9-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide23 (8.5 mg, 33%) as a white solid. MS (ESI, m/e) Calculated 486.1539;Found 487.1 [M+H]⁺.

Synthesis of(S)—N-(9-((4-Hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide25 (I-16)

To a solution of(S)—N-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide21 (24 mg, 51 μmol), 4-ethynyltetrahydro-2H-pyran-4-ol 24 (19.4 mg,0.153 mmol), CuI (1 mg, 5.1 μmol) and Pd(PPh₃)₄ (5.9 mg, 5.1 μmol) inanhydrous DMF (1 mL) was added triethylamine (31 mg, 43 μL, 0.307 mmol).The reaction mixture was then purged with nitrogen for 1 minute, sealedand heated at 70° C. for 16 hrs, cooled down to ambient temperature anddiluted with ethyl acetate (60 mL). The reaction mixture was washed withbrine, dried over anhydrous magnesium sulfate, filtered and concentratedunder reduced pressure and the resulting residue was purified by reverseHPLC using a gradient of 27 to 67% acetonitrile in water buffered with0.1% formic acid. The desired fractions were combined and lyophilized toafford(S)—N-(9-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide25 (13.6 mg, 52%) as a white solid. MS (ESI, m/e) Calculated 514.1852;Found 515.1 [M+H]⁺.

Synthesis of(S)—N-(9-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetra-hydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide29 (I-14)

Synthesis of tert-Butyl(S)-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate27

To a solution of tert-butyl(S)-(9-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate8 (32 mg, 0.086 mmol) and 2-methylbut-3-yn-2-ol 26 (22 mg, 0.257 mmol)in anhydrous DMF (1 mL) were added Pd(PPh₃)₄(9.9 mg, 8.6 μmol), CuI (1.6mg, 8.6 μmol) and triethylamine (52 mg, 72 μL, 0.515 mmol). The reactionmixture was then purged with nitrogen for 1 minute, sealed and heated at70° C. for 22 hrs, cooled down to ambient temperature and diluted withethyl acetate (80 mL). The resulting organic mixture was washed withwater (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The residue obtainedwas purified by reverse phase HPLC using a gradient of 20 to 70%acetonitrile in water buffered with 0.1% formic acid. The desiredfractions were combined and diluted with ethyl acetate, washed withsaturated sodium bicarbonate aqueous solution, brine, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to afford tert-butyl(S)-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate27 (32 mg, >95% yield). MS (ESI, m/e) Calculated 375.1794; Found 320.0[M-^(t)Bu+H]⁺.

Synthesis of(S)-3-Amino-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride 28

To a solution of tert-butyl(S)-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate27 (32 mg, 0.086 mmol) in anhydrous 1,4-dioxane (2 mL) was addedhydrogen chloride solution (0.2 mL, 4M in dioxane, 0.8 mmol). Thereaction mixture was stirred at ambient temperature for 15 hrs, then anadditional amount of hydrogen chloride solution (0.6 mL, 4M in dioxane,2.4 mmol) was added, and the reaction mixture was allowed to stir foranother 9 hrs. All solvents were removed under reduced pressure toafford(S)-3-amino-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride 28 (27 mg, 100%) as a pale yellow solid, which wasdirectly used in the next step. MS (ESI, m/e) Calculated 275.1270; Found276.1 [M+H]⁺.

Synthesis of(S)—N-(9-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetra-hydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide29

To a solution of(S)-3-amino-9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride 28 (27 mg, 0.0858 mmol) and 4-phenoxypicolinic acid 13 (28mg, 0.129 mmol) in anhydrous DMF (1.4 mL) was addeddiisopropylethylamine (55.5 mg, 74 μL, 0.429 mmol) followed by HATU(48.9 mg, 0.129 mmol). The resulting reaction mixture was stirred atambient temperature for 14 hrs. A drop of water was added, and thesolution was directly purified by reverse HPLC using a gradient of 40 to80% acetonitrile in water buffered with 0.1% formic acid. The desiredfractions were combined and lyophilized to afford(S)—N-(9-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide29 (22.1 mg, 55%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d,J=7.1 Hz, 1H), 8.46 (dd, J=5.6, 0.5 Hz, 1H), 8.23 (d, J=5.0 Hz, 1H),7.62 (dd, J=2.6, 0.5 Hz, 1H), 7.48-7.38 (m, 2H), 7.31-7.22 (m, 1H), 7.19(d, J=5.0 Hz, 1H), 7.12-7.06 (m, 2H), 6.97 (dd, J=5.6, 2.5 Hz, 1H), 5.03(dt, J=11.3, 7.2 Hz, 1H), 4.89 (dd, J=9.6, 7.2 Hz, 1H), 4.39 (dd,J=11.3, 9.6 Hz, 1H), 3.52 (s, 3H), 1.63 (s, 6H). MS (ESI, m/e)Calculated 472.1747; Found 473.1 [M+H]⁺.

General Procedure to Prepare 7-Substituted Pyridooxaazepine CompoundsVIII Method A:

7-substituted pyridooxaazepine compounds were prepared according to theMethod A general procedure set forth above. Versatile intermediate I canbe coupled with a variety of groups, via metal-catalyzed (for examplepalladium-catalyzed) cross coupling reactions as is known to those ofskill in the art. In particular alkynyl groups can be readily coupled tothe pyridooxezepine ring according to this general scheme by adaptingthe procedures set forth below. By way of example, compounds made bymethod A include I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-41,I-42, I-43, I-44, I-45, I-46 and I-47.

(S)—N-(7-(4,4-difluoro-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-32)

This compound was obtained from the corresponding aldehyde which wasobtained by the oxidation of(S)—N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide. MS (ESI, m/z)Calculated 506.1766; Found [M+1]⁺ 507.1. ¹H NMR (400 MHz, Chloroform-d)δ (ppm) 8.93 (d, J=7.0 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.61 (d, J=2.5Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.46-7.38 (m, 2H), 7.36 (d, J=8.1 Hz,1H), 7.28-7.23 (m, 1H), 7.10-7.05 (m, 2H), 6.96 (dd, J=5.6, 2.5 Hz, 1H),5.25 (dd, J=48.3, 10.7 Hz, 1H), 5.02 (dt, J=11.4, 6.9 Hz, 1H), 4.79(ddd, J=9.7, 6.8, 1.3 Hz, 1H), 4.37 (dd, J=11.4, 9.7 Hz, 1H), 3.53 (s,3H), 1.62-1.59 (m, 3H), 1.55-1.51 (m, 3H).

N-((3S)-5-methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-33)

MS (ESI, m/z) Calculated 512.1308; Found [M+1]⁺ 513.0. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 9.03-8.89 (m, 1H), 8.45 (dt, J=5.7, 0.6 Hz, 1H),7.61 (dt, J=2.6, 0.7 Hz, 1H), 7.52-7.46 (m, 1H), 7.46-7.38 (m, 2H), 7.35(dd, J=8.1, 4.8 Hz, 1H), 7.28-7.24 (m, 1H), 7.10-7.04 (m, 2H), 6.96 (dd,J=5.6, 2.5 Hz, 1H), 5.18-4.99 (m, 1H), 4.94 (t, J=6.3 Hz, 1H), 4.81 (dt,J=9.7, 7.2 Hz, 1H), 4.43-4.31 (m, 1H), 3.54-3.46 (m, 3H), 3.23-2.86 (m,1H).

(S)-5-(2-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide(I-34)

MS (ESI, m/z) Calculated 478.1765; Found [M+1]⁺ 479.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 12.18 (s, 1H), 8.10 (d, J=7.0 Hz, 1H), 7.44 (s,1H), 7.27 (d, J=8.1 Hz, 1H), 7.26-7.18 (m, 2H), 7.10-6.97 (m, 2H), 5.01(dt, J=11.4, 7.0 Hz, 1H), 4.75 (dd, J=9.8, 7.0 Hz, 1H), 4.32 (dd,J=11.4, 9.8 Hz, 1H), 4.20 (s, 2H), 3.50 (s, 3H), 1.64 (s, 6H).

(S)-5-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide(I-35)

MS (ESI, m/z) Calculated 478.1765; Found [M+1]⁺ 479.1.

(S)-5-benzyl-N-(7-((3,3-difluoro-1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide(I-36)

MS (ESI, m/z) Calculated 508.1671; Found [M+1]⁺ 509.5. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 12.33 (s, 1H), 8.11 (d, J=7.0 Hz, 1H), 7.42 (d,J=8.1 Hz, 1H), 7.31-7.17 (m, 6H), 5.02 (dt, J=11.3, 6.9 Hz, 1H), 4.73(dd, J=9.8, 6.9 Hz, 1H), 4.33 (dd, J=11.4, 9.8 Hz, 1H), 4.14 (s, 2H),3.51 (s, 1H), 3.46 (s, 3H), 3.27-3.11 (m, 2H), 2.99 (dtd, J=13.0, 11.7,4.0 Hz, 2H).

5-Benzyl-N-((3S)-5-methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide(I-37)

MS (ESI, m/z) Calculated 500.1420; Found [M+1]⁺ 501.5. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 9.20 (s, 0.5H), 8.11 (dd, J=6.9, 3.2 Hz, 1H), 7.47(dd, J=8.1, 1.2 Hz, 1H), 7.36-7.29 (m, 3H), 7.28 (d, J=4.0 Hz, 2H), 6.27(q, J=5.7 Hz, 0.5H), 5.13-4.89 (m, 2H), 4.78 (ddd, J=9.8, 6.8, 3.0 Hz,1H), 4.35 (ddd, J=11.3, 9.9, 1.2 Hz, 1H), 4.16 (s, 2H), 3.48 (m, 3H).

(S)-4-Fluoro-1-(4-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(I-38)

MS (ESI, m/z) Calculated 495.1718; Found [M+1]⁺ 496.5. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 7.64 (d, J=6.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H),7.25-7.16 (m, 4H), 7.07-6.98 (m, 2H), 5.17 (s, 2H), 5.00 (dt, J=11.3,6.7 Hz, 1H), 4.82 (dd, J=9.7, 6.9 Hz, 1H), 4.28 (dd, J=11.3, 9.7 Hz,1H), 3.49 (s, 3H), 1.62 (s, 6H).

(S)—N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-(3-fluorophenoxy)picolinamide(I-39)

This compound was obtained from the desilyation of(S)-4-(3-fluorophenoxy)-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide.MS (ESI, m/z) Calculated 432.1234; Found [M+1]⁺ 433.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.94 (d, J=7.0 Hz, 1H), 8.49 (dd, J=5.6, 0.5 Hz,1H), 7.63 (dd, J=2.5, 0.5 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.42-7.32 (m,2H), 7.02-6.94 (m, 2H), 6.88 (ddt, J=8.1, 2.2, 0.8 Hz, 1H), 6.82 (dt,J=9.3, 2.3 Hz, 1H), 5.03 (dt, J=11.4, 6.9 Hz, 1H), 4.79 (dd, J=9.7, 6.9Hz, 1H), 4.38 (dd, J=11.4, 9.7 Hz, 1H), 3.54 (s, 3H), 3.17 (s, 1H).

(S)-4-fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(prop-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(I-41)

MS (ESI, m/z) Calculated 451.1456; Found [M+1]⁺ 452.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 7.66 (d, J=6.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H),7.24 (d, J=1.2 Hz, 1H), 7.21 (td, J=4.3, 1.4 Hz, 3H), 7.09-6.97 (m, 2H),5.19 (s, 2H), 5.01 (dt, J=11.2, 6.7 Hz, 1H), 4.83 (dd, J=9.7, 7.0 Hz,1H), 4.29 (dd, J=11.3, 9.7 Hz, 1H), 3.51 (s, 3H), 2.08 (s, 3H).

(S)-4-fluoro-1-((6-fluoropyridin-2-yl)methyl)-N-(5-methyl-4-oxo-7-(prop-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(I-42)

MS (ESI, m/z) Calculated 452.1408; Found [M+1]⁺ 453.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 7.85-7.75 (m, 1H), 7.65 (d, J=6.4 Hz, 1H), 7.50(d, J=4.7 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H),7.06-7.00 (m, 1H), 6.94-6.88 (m, 1H), 5.28 (s, 2H), 5.02 (dt, J=11.2,6.7 Hz, 1H), 4.83 (dd, J=9.7, 6.9 Hz, 1H), 4.29 (dd, J=11.2, 9.7 Hz,1H), 3.52 (s, 3H), 2.09 (s, 3H).

N-((3S)-5-methyl-4-oxo-7-(4,4,4-trifluoro-3-hydroxy-3-methylbut-1-yn-1-yl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-43)

MS (ESI, m/z) Calculated 526.1464; Found [M+1]⁺ 527.3. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 9.01 (dd, J=23.0, 6.7 Hz, 1H), 8.44 (dt, J=5.6,0.7 Hz, 1H), 7.62 (ddd, J=3.3, 2.5, 0.5 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H),7.45-7.38 (m, 2H), 7.30-7.26 (m, 1H), 7.25-7.21 (m, 1H), 7.07 (dq,J=7.3, 1.0 Hz, 2H), 6.94 (ddd, J=5.6, 2.5, 1.5 Hz, 1H), 5.19 (ddt,J=51.2, 11.3, 6.7 Hz, 1H), 4.85 (ddd, J=19.7, 9.7, 6.7 Hz, 1H), 4.35(ddd, J=11.5, 9.7, 1.8 Hz, 1H), 3.49-3.37 (m, 3H), 1.80-1.72 (m, 3H).

(S)—N-(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-44)

MS (ESI, m/z) Calculated 470.1590; Found [M+1]⁺ 471.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.92 (d, J=7.0 Hz, 1H), 8.44 (dd, J=5.6, 0.5 Hz,1H), 7.61 (dd, J=2.5, 0.5 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.44-7.37 (m,2H), 7.28 (d, J=8.1 Hz, 1H), 7.26-7.22 (m, 1H), 7.09-7.04 (m, 2H), 6.95(dd, J=5.6, 2.6 Hz, 1H), 5.01 (dt, J=11.4, 7.0 Hz, 1H), 4.86 (dq, J=7.4,5.6 Hz, 4H), 4.78 (dd, J=9.7, 6.9 Hz, 1H), 4.34 (dd, J=11.4, 9.7 Hz,1H), 4.11 (tt, J=8.5, 7.4 Hz, 1H), 3.52 (s, 3H).

(S)—N-(7-(3,3-difluoro-3-(oxetan-3-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-45)

MS (ESI, m/z) Calculated 520.1558; Found [M+1]⁺ 521.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.92 (d, J=6.9 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H),7.62 (d, J=2.5 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.46-7.37 (m, 3H),7.29-7.23 (m, 1H), 7.11-7.04 (m, 2H), 6.96 (dd, J=5.6, 2.5 Hz, 1H), 5.02(dt, J=11.4, 6.8 Hz, 1H), 4.88-4.75 (m, 5H), 4.39 (dd, J=11.4, 9.8 Hz,1H), 3.73 (dtdd, J=14.6, 12.5, 8.1, 6.5 Hz, 1H), 3.54 (s, 3H).

N-((3S)-7-(3-Amino-4,4,4-trifluoro-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-46)

MS (ESI, m/z) Calculated 525.1624; Found [M+1]⁺ 526.0. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.91 (d, J=7.0 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H),7.61 (d, J=2.4 Hz, 1H), 7.50-7.37 (m, 3H), 7.31 (d, J=8.2 Hz, 1H),7.27-7.21 (m, 1H), 7.10-7.03 (m, 2H), 6.95 (dd, J=5.6, 2.5 Hz, 1H), 5.00(dt, J=11.4, 6.9 Hz, 1H), 4.78 (dd, J=9.7, 6.8 Hz, 1H), 4.35 (dd,J=11.4, 9.7 Hz, 1H), 3.52 (s, 3H), 1.92 (s, 2H), 1.66 (s, 3H).

(S)—N-(5-Methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxyppicolinamide(I-47)

MS (ESI, m/z) Calculated 498.1903; Found [M+1]⁺ 499.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.92 (d, J=7.0 Hz, 1H), 8.44 (dd, J=5.6, 0.5 Hz,1H), 7.61 (dd, J=2.5, 0.5 Hz, 1H), 7.47-7.37 (m, 3H), 7.29-7.22 (m, 2H),7.10-7.03 (m, 2H), 6.95 (dd, J=5.6, 2.5 Hz, 1H), 5.01 (dt, J=11.3, 6.9Hz, 1H), 4.78 (dd, J=9.7, 6.9 Hz, 1H), 4.33 (dd, J=11.4, 9.7 Hz, 1H),3.96 (ddd, J=11.7, 5.3, 3.8 Hz, 2H), 3.59-3.49 (m, 5H), 2.88 (tt, J=8.7,4.1 Hz, 1H), 1.98-1.87 (m, 2H), 1.81 (ddt, J=13.7, 9.2, 4.4 Hz, 2H).

Step 1: Synthesis of Intermediate (VI)

Intermediate I (0.1 mmol, 1 eq), substituted ethyne (0.2 to 0.3 mmol, 2to 3 eq), Pd(PPh₃)₄ (0.01 mmol, 0.1 eq) and CuI (0.01 mmol, 0.1 eq) inanhydrous DMF (1 mL) in a vial was added Et₃N (0.4 mmol, 4 eq). Thereaction solution was purged with nitrogen for 1 minute, then sealed andheated at 70° C. for 14 to 24 hours. Reaction solution was cooled toambient temperature, diluted with ethyl acetate (100 mL), washed withbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under the reduced pressure. Residue obtained was purifiedby silica gel chromatography or reverse HPLC (mobile phase A: water with0.1% HCOOH; mobile phase B: acetonitrile with 0.1% HCOOH) to affordintermediate VI.

Step 2: Synthesis of Intermediate (VII)

Intermediate VI (1 eq) was dissolved in dichloromethane, then TFA(concentration: 10% in dichloromethane) or HCl (40 eq, 4N in dioxane)was added. The resulting solution was stirred at ambient temperatureuntil all starting material disappeared (monitored by reverse HPLC). Allsolvents were removed under the reduced pressure to afford crude productof intermediate VII which was directly used in next step.

Step 3: Synthesis of Final Product (VIII)

Intermediate VII (1 eq), corresponding acid (1.2 eq), anddiisopropylethylamine (5 eq) were dissolved in DMF (concentration 0.05Mto 0.1M), then HATU (1.2 eq) was added. The resulting solution wasstirred at ambient temperature for 14 to 24 hours. Reaction solution wasadded brine and ethyl acetate. Organic layer was separated and driedover anhydrous magnesium sulfate, filtered, and concentrated under thereduced pressure. Residue obtained was purified by silica gelchromatography or reverse HPLC (mobile phase A: water with 0.1% HCOOH;mobile phase B: acetonitrile with 0.1% HCOOH) to afford final product(VIII).

Exemplary 7-substituted pyridooxaazepine compounds also were preparedaccording to the general procedure Method B, set forth below.

Method B:

Step 1: Synthesis of Intermediate IX

Intermediate I was dissolved in 10% trifluoracetic acid indichloromethane (0.1M) and stirred at room temperature for about 3hours. All solvents were removed under the reduced pressure to affordcrude trifluoracetic acid salt of IX, which was used directly in nextstep. MS (ESI, m/z) Calculated 270.9956; Found [M+1]⁺ 271.9.

Step 2: Synthesis of Intermediate X

Intermediate IX (1 eq), corresponding acid (1.2 eq), anddiisopropylethylamine (5 eq) were dissolved in DMF (concentration 0.05Mto 0.1M), then HATU (1.2 eq) was added. The resulting solution wasstirred at ambient temperature for 14 to 24 hours. Reaction solution wasadded brine and ethyl acetate. Organic layer was separated and driedover anhydrous magnesium sulfate, filtered, and concentrated under thereduced pressure. Residue obtained was purified by silica gelchromatography or reverse HPLC (mobile phase A: water with 0.1% HCOOH;mobile phase B: acetonitrile with 0.1% HCOOH) to afford intermediate(X).

Step 2: Synthesis of Final Product VIII

Intermediate X (0.1 mmol, 1 eq), substituted ethyne (0.2 to 0.3 mmol, 2to 3 eq), Pd(PPh₃)₄(0.01 mmol, 0.1 eq) and CuI (0.01 mmol, 0.1 eq) inanhydrous DMF (1 mL) in a vial was added Et₃N (0.4 mmol, 4 eq). Thereaction solution was purged with nitrogen for 1 minute, then sealed andheated at 70° C. for 14 to 24 hours. Reaction solution was cooled toambient temperature, diluted with ethyl acetate (100 mL), washed withbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under the reduced pressure. Residue obtained was purifiedby silica gel chromatography or reverse HPLC (mobile phase A: water with0.1% HCOOH; mobile phase B: acetonitrile with 0.1% HCOOH) to affordfinal product VIII.

Compounds synthesized by method B include compounds I-17, I-19, I-20,I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30 and I-40.

((S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-17)

MS (ESI, m/z) Calculated 486.1539; Found [M+1]⁺ 487.1.

(S)-4-(4-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide(I-19)

MS (ESI, m/z) Calculated 504.1445; Found [M+1]⁺ 505.1.

(S)—N-(7-((3-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2,b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-20)

To a solution of((S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (9.5 mg, 0.0195mmol) in anhydrous dichloromethane (1 mL) at −78° C. was addedDeoxo-Fluor (8.6 mg, 7.2 uL, 0.039 mmol). The resulting solution wasstirred at this temperature for 30 minutes, then additional Deoxo-Fluor(4.3 mg, 3.6 uL, 0.020 mmol) was added and stirred for additional 15minutes. Saturated sodium bicarbonate solution (0.1 mL) was addedfollowed by dichloromethane (60 mL). Solution was washed with water (15mL), brine (15 mL) and dried over anhydrous magnesium sulfate, filteredand concentrated under the reduced pressure. Residue was purified byreverse HPLC (40 to 70% acetonitrile in water with 0.1% formic acid).Desired fractions were combined, diluted with ethyl acetate, washed witha little saturated sodium bicarbonate aqueous solution, brine, driedover anhydrous magnesium sulfate, filtered, and concentrated under thereduced pressure to afford(S)—N-(7-((3-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2,b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(2.5 mg, 26%) as a white solid. MS (ESI, m/z) Calculated 488.1496; Found[M+1]⁺ 489.1. ¹H NMR (400 MHz, Chloroform-d) δ (ppm) 8.98-8.87 (m, 1H),8.48-8.37 (m, 1H), 7.64-7.52 (m, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.46-7.39(m, 2H), 7.39-7.33 (m, 1H), 7.08 (dd, J=2.0, 1.3 Hz, 1H), 7.07 (dd,J=2.1, 1.0 Hz, 1H), 7.05-7.01 (m, 1H), 6.96 (dd, J=5.6, 2.6 Hz, 1H),5.12-4.86 (m, 5H), 4.79 (dd, J=9.7, 6.8 Hz, 1H), 4.38 (dd, J=11.4, 9.7Hz, 1H), 3.55 (m, 3H).

(S)-4-(3-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide(I-21)

MS (ESI, m/z) Calculated 490.1652; Found [M+1]⁺ 491.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) δ 8.93 (d, J=7.0 Hz, 1H), 8.48 (dd, J=5.6, 0.6 Hz,1H), 7.62 (dd, J=2.5, 0.5 Hz, 1H), 7.38 (td, J=8.3, 6.5 Hz, 1H), 7.29(s, 1H), 7.01-6.92 (m, 2H), 6.87 (ddt, J=8.2, 2.2, 0.8 Hz, 1H), 6.81(dt, J=9.4, 2.4 Hz, 1H), 5.02 (dt, J=11.4, 7.0 Hz, 1H), 4.83-4.71 (m,1H), 4.34 (dd, J=11.4, 9.7 Hz, 1H), 3.53 (s, 3H), 1.64 (s, 6H).

(S)-4-(3-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide(I-22)

MS (ESI, m/z) Calculated 504.1445; Found [M+1]⁺ 505.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 9.01-8.86 (m, 1H), 8.53-8.41 (m, 1H), 7.65-7.54(m, 1H), 7.53-7.46 (m, 1H), 7.38 (td, J=8.3, 6.5 Hz, 1H), 7.35-7.30 (m,1H), 7.14-6.92 (m, 2H), 6.87 (ddt, J=8.2, 2.3, 0.8 Hz, 1H), 6.84-6.78(m, 1H), 5.06 (dt, J=11.4, 6.9 Hz, 1H), 4.97 (td, J=6.2, 5.8, 0.9 Hz,2H), 4.86-4.76 (m, 3H), 4.71 (dt, J=6.9, 0.7 Hz, 1H), 4.37 (dd, J=11.4,9.7 Hz, 1H), 3.54 (d, J=13.5 Hz, 3H).

(S)—N-(7-((3-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-(3-fluorophenoxy)picolinamide(I-23)

To a solution of(S)-4-(3-fluorophenoxy)-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide(12.4 mg, 0.0246 mmol) in anhydrous dichloromethane (1 mL) at −78° C.was added Deoxo-Fluor (16.3 mg, 14 uL, 0.0737 mmol). The resultingsolution was stirred at this temperature for 30 minutes, then saturatedsodium bicarbonate solution (0.2 mL) was added followed bydichloromethane (80 mL). Solution was washed with water (15 mL), brine(15 mL) and dried over anhydrous magnesium sulfate, filtered, andconcentrated under the reduced pressure. Residue was purified by reverseHPLC (40 to 70% acetonitrile in water with 0.1% formic acid). Desiredfractions were combined, diluted with ethyl acetate, washed with alittle saturated sodium bicarbonate aqueous solution, brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under thereduced pressure to afford(S)—N-(7-((3-fluorooxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-(3-fluorophenoxy)picolinamide(4.7 mg, 38%) as a white solid. MS (ESI, m/z) Calculated 506.1402; Found[M+1]⁺ 507.0. ¹H NMR (400 MHz, Chloroform-d) δ (ppm) 8.99-8.85 (m, 1H),8.53-8.41 (m, 1H), 7.67-7.60 (m, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.44-7.34(m, 2H), 7.03-6.92 (m, 2H), 6.92-6.85 (m, 1H), 6.85-6.79 (m, 1H),5.10-4.88 (m, 5H), 4.81 (dd, J=9.7, 6.8 Hz, 1H), 4.39 (dd, J=11.4, 9.7Hz, 1H), 3.65-3.40 (m, 3H).

(S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide(I-24)

MS (ESI, m/z) Calculated 460.1859; Found [M+1]⁺ 461.1. ¹H NMR (400 MHz,Methanol-d4) δ (ppm) 7.61 (d, J=8.2 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H),7.35-7.15 (m, 5H), 5.03 (dd, J=11.5, 7.1 Hz, 1H), 4.67 (dd, J=9.8, 7.1Hz, 1H), 4.51 (dd, J=11.6, 9.8 Hz, 1H), 4.17 (s, 2H), 3.45 (s, 3H), 1.58(s, 6H).

(S)-5-benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide(I-25)

MS (ESI, m/z) Calculated 474.1652; Found [M+1]⁺ 475.1. ¹H NMR (400 MHz,Methanol-d4) δ (ppm) 7.64 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H),7.36-7.20 (m, 5H), 5.04 (dd, J=11.5, 7.0 Hz, 1H), 4.89 (d, J=0.9 Hz,2H), 4.73-4.69 (m, 2H), 4.67 (dd, J=7.2, 2.7 Hz, 1H), 4.52 (dd, J=11.6,9.8 Hz, 1H), 4.16 (s, 2H), 3.46 (s, 3H).

(S)—N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-26)

MS (ESI, m/z) Calculated 484.1747; Found [M+1]⁺ 485.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.93 (d, J=7.0 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H),7.61 (d, J=2.5 Hz, 1H), 7.50-7.37 (m, 3H), 7.30 (d, J=8.1 Hz, 1H),7.27-7.23 (m, 1H), 7.11-7.03 (m, 2H), 6.95 (dd, J=5.6, 2.5 Hz, 1H), 5.03(dt, J=11.4, 6.9 Hz, 1H), 4.79 (dd, J=9.7, 7.0 Hz, 1H), 4.35 (dd,J=11.4, 9.7 Hz, 1H), 3.52 (s, 3H), 2.65-2.52 (m, 2H), 2.44 (s, 1H),2.40-2.30 (m, 2H), 1.96-1.85 (m, 2H).

(S)-4-(4-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide(I-27)

MS (ESI, m/z) Calculated 490.1652; Found [M+1]⁺ 491.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.92 (d, J=7.0 Hz, 1H), 8.45 (dd, J=5.6, 0.6 Hz,1H), 7.57 (dd, J=2.6, 0.5 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.28 (d,J=8.1 Hz, 1H), 7.14-7.08 (m, 2H), 7.08-7.02 (m, 2H), 6.93 (dd, J=5.6,2.6 Hz, 1H), 5.01 (dt, J=11.3, 7.0 Hz, 1H), 4.82-4.72 (m, 1H), 4.34 (dd,J=11.4, 9.7 Hz, 1H), 3.52 (d, J=1.3 Hz, 3H).

(S)-4-(2-fluorophenoxy)-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)picolinamide(I-28)

MS (ESI, m/z) Calculated 490.1652; Found [M+1]⁺ 491.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.95 (d, J=7.0 Hz, 1H), 8.48 (dd, J=5.6, 0.5 Hz,1H), 7.59 (dt, J=2.6, 0.6 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.30-7.23 (m,4H), 7.23-7.21 (m, 1H), 7.21-7.17 (m, 2H), 6.98 (ddd, J=5.6, 2.6, 0.5Hz, 1H), 5.03 (dt, J=11.4, 6.9 Hz, 1H), 4.79 (dd, J=9.7, 6.9 Hz, 1H),4.35 (dd, J=11.4, 9.7 Hz, 1H), 4.13 (q, J=7.1 Hz, 1H), 3.53 (s, 3H),1.65 (s, 6H).

(S)—N-(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-fluoro-1-(4-fluorobenzyl)-1H-pyrazole-3-carboxamide(I-40)

This compound was obtained from the desilylation of(S)-4-fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide.MS (ESI, m/z) Calculated 437.1299; Found [M+1]⁺ 438.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 7.66 (d, J=6.4 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H),7.35 (d, J=8.1 Hz, 1H), 7.25-7.18 (m, 3H), 7.11-7.01 (m, 2H), 5.19 (s,2H), 5.03 (dt, J=11.3, 6.7 Hz, 1H), 4.84 (dd, J=9.7, 6.8 Hz, 1H), 4.32(dd, J=11.3, 9.7 Hz, 1H), 3.53 (s, 3H), 3.16 (s, 1H).

General Synthesis of 7-Ethynyl Pyridoazepine Compound XI

As will be readily appreciated by those of skill in the art, thesynthesis of compound XI illustrated is applicable to compounds having avariety of R groups.

6-Amino-5-bromopyridin-2-ol

6-Aminopyridin-2-ol (11 g, 0.1 mmol) was dissolved in acetic acid (220mL), then bromine (16 g, 5.12 mL, 0.1 mmol) was added at ambienttemperature. The resulting solution was stirred at this temperature for40 minutes. Water (200 mL) was added, and solution was filtered throughCelite. Filtrate was extracted with ethyl acetate (3×400 mL). Combinedorganic layer was washed with water (2×100 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated under the reduced pressureto afford crude product of 6-Amino-5-bromopyridin-2-ol (8.3 g) as a palebrown solid, which was used directly in next step without furtherpurification. MS (ESI, m/z) Calculated 187.9585; Found [M+1]⁺188.9. ¹HNMR (400 MHz, DMSO-d6) δ (ppm) 10.79 (s, 1H), 7.38 (d, J=8.8 Hz, 1H),5.93 (s, 2H), 5.60 (d, J=8.8 Hz, 1H).

3-Bromo-6-methoxypyridin-2-amine

Crude material of 6-Amino-5-bromopyridin-2-ol (8.3 g, 43.9 mmol) wasdissolved in acetone (130 mL), then potassium hydroxide (7.4 g, 0.132mol) was added followed by dimethyl sulfate (7.20 g, 5.4 mL, 57.1 mmol).The reaction solution was stirred at ambient temperature for 4 hours.All solvents were removed under the reduced pressure. Residue was addedbrine (100 mL) and extracted with ethyl acetate (3×300 mL). Combinedorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated under the reduced pressure. Residue obtained was purifiedby silica gel chromatography using a gradient of 0 to 30% ethyl acetatein hexane to afford 3-bromo-6-methoxypyridin-2-amine (4.09 g, 20% over 2steps) as a white solid. MS (ESI, m/z) Calculated 201.9742; Found[M+1]⁺202.9. ¹H NMR (400 MHz, Chloroform-d) δ (ppm) 7.48 (d, J=8.4 Hz,1H), 6.02 (d, J=8.3 Hz, 1H), 4.73 (s, 2H), 3.82 (s, 3H).

6-Methoxy-3-vinylpyridin-2-amine

Pd(PPh₃)₄(1.17 g, 1.01 mmol) was added to the solution of3-bromo-6-methoxypyridin-2-amine (4.09 g, 20.3 mmol) andtributyl(vinyl)stannane (9.64 g, 30.4 mmol) in anhydrous toluene (66mL). The solution was purged with nitrogen for 1 min, then sealed andheated at 110° C. for 16 hours. Reaction solution was cooled to ambienttemperature. Potassium fluoride aqueous solution (100 mL, 1M) was addedfollowed by ethyl acetate (500 mL). The solution was filtered throughCelite, washed with ethyl acetate. Organic was separated, washed withbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under the reduced pressure. Residue obtained was purifiedby silica gel chromatography using a gradient of 0 to 10% ethyl acetatein hexane to afford 6-methoxy-3-vinylpyridin-2-amine (2.09 g, 69%) as apale-yellow liquid. MS (ESI, m/z) Calculated 150.0793; Found[M+1]⁺150.9. ¹H NMR (400 MHz, Chloroform-d) δ (ppm) 7.46 (dd, J=8.2, 0.6Hz, 1H), 6.57 (ddt, J=17.4, 11.1, 0.6 Hz, 1H), 6.14 (dd, J=8.2, 0.6 Hz,1H), 5.49 (dd, J=17.4, 1.2 Hz, 1H), 5.21 (dd, J=11.1, 1.2 Hz, 1H), 4.45(s, 2H), 3.85 (s, 3H).

tert-Butyl (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoate

To a solution of(S)-4-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid(20 g, 59.3 mmol) in anhydrous benzene (600 mL) was added copper(II)acetate (2.7 g, 14.8 mmol). The resulting solution was stirred atambient temperature under nitrogen for 2 hours, then lead tetraacetate(55.3 g, 0.119 mol) was added. The resulting solution was refluxed undernitrogen for 14 hours before it was cooled to ambient temperature.Reaction solution was filtered through Celite and washed with ethylacetate (1200 mL). Organic layer was washed with water (2×300 mL), brine(300 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated under the reduced pressure. Residue obtained was purifiedby silica gel chromatography using a gradient of 0 to 10% ethyl acetatein hexane to afford tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoate (4.3 g, 25%) as a pale-yellow liquid. MS(ESI, m/z) Calculated 291.1471; Found [M-^(t)Bu+1]⁺ 236.0. ¹H NMR (400MHz, Chloroform-d) δ (ppm) 7.44-7.27 (m, 5H), 5.90 (ddd, J=16.3, 10.4,5.3 Hz, 1H), 5.44 (d, J=8.1 Hz, 1H), 5.34 (ddd, J=17.2, 1.8, 0.7 Hz,1H), 5.24 (ddd, J=10.4, 1.8, 0.7 Hz, 1H), 5.12 (s, 2H), 4.86-4.74 (m,1H), 1.46 (s, 9H).

(S)-2-(((Benzyloxy)carbonyl)amino)but-3-enoic acid

To a solution of tert-butyl(S)-2-(((benzyloxy)carbonyl)amino)but-3-enoate (4.3 g, 14.8 mmol) inanhydrous dichloromethane (340 mL) at 0° C. was added trifluoraceticacid (50.5 g, 34 mL, 0.443 mol). The resulting solution was stirred atambient temperature for 16 hours. All solvents were removed under thereduced pressure to afford (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoicacid (3.3 g, 95%) as a white solid. MS (ESI, m/z) Calculated 235.0845;Found [M-1]⁺ 234.1. ¹H NMR (400 MHz, DMSO-d6) δ (ppm) δ 12.80 (s, 1H),7.83 (d, J=8.2 Hz, 1H), 7.42-7.25 (m, 5H), 5.91 (ddd, J=16.8, 10.4, 6.1Hz, 1H), 5.33 (dt, J=17.2, 1.5 Hz, 1H), 5.21 (dt, J=10.4, 1.4 Hz, 1H),5.05 (s, 2H), 4.62 (ddt, J=7.8, 6.1, 1.7 Hz, 1H).

Benzyl(S)-(1-((6-methoxy-3-vinylpyridin-2-yl)amino)-1-oxobut-3-en-2-yl)carbamate

To a cloudy solution of (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoicacid (1.75 g, 7.55 mmol) in anhydrous dichloromethane (35 mL) at 0° C.was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.01 g, 1 mL, 7.55g) dropwise, and stirred at this temperature for 30 minutes. Then6-methoxy-3-vinylpyridin-2-amine (1.03 g, 6.87 mmol) in anhydrousdichloromethane (5 mL) was added dropwise followed by triethylamine(0.76 g, 1.05 mL, 7.55 mmol). The resulting solution was stirred atambient temperature for additional 2 hours, and dichloromethane (150 mL)was added. The solution was washed with a little HCl aqueous solution(1N), sodium bicarbonate aqueous solution, brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated under the reducedpressure. Residue obtained was purified by silica gel chromatographyusing a gradient of 0 to 50% ethyl acetate in hexane to afford benzyl(S)-(1-((6-methoxy-3-vinylpyridin-2-yl)amino)-1-oxobut-3-en-2-yl)carbamate(568 mg, 23%) as a pale-yellow liquid. MS (ESI, m/z) Calculated367.1532; Found [M+1]⁺ 368.1. ¹H NMR (400 MHz, Chloroform-d) δ (ppm)7.75 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.43-7.27 (m, 5H), 6.63 (d, J=8.5Hz, 1H), 6.54 (dd, J=17.5, 11.1 Hz, 1H), 6.02 (ddd, J=16.9, 10.2, 6.3Hz, 1H), 5.79 (s, 1H), 5.59 (dd, J=17.4, 0.9 Hz, 1H), 5.47 (d, J=17.0Hz, 1H), 5.37 (d, J=10.1 Hz, 1H), 5.30 (d, J=11.0 Hz, 1H), 5.14 (d,J=1.3 Hz, 2H), 3.98-3.72 (s, 3H).

Benzyl(S)-(2-methoxy-8-oxo-8,9-dihydro-7H-pyrido[2,3-b]azepin-7-yl)carbamate

To a suspension solution of benzyl(S)-(1-((6-methoxy-3-vinylpyridin-2-yl)amino)-1-oxobut-3-en-2-yl)carbamate(573 mg, 1.56 mmol) in anhydrous toluene (78 mL) was added Grubb's2^(nd) generation catalyst (133 mg, 0.156 mmol). The solution was purgedwith nitrogen for 1 minute, then heated at 80° C. under nitrogen for 15hours. Reaction solution was cooled to ambient temperature. All solventswere removed under the reduced pressure. Residue obtained was purifiedby silica gel chromatography using a gradient of 0 to 30% ethyl acetatein hexane to afford benzyl(S)-(2-methoxy-8-oxo-8,9-dihydro-7H-pyrido[2,3-b]azepin-7-yl)carbamate(343 mg, 65%) as a white solid. MS (ESI, m/z) Calculated 339.1219; Found[M+1]⁺ 340.0. ¹H NMR (400 MHz, Chloroform-d) δ (ppm) 7.97 (s, 1H), 7.55(d, J=8.4 Hz, 1H), 7.44-7.27 (m, 5H), 6.63-6.53 (m, 2H), 6.22 (d, J=6.2Hz, 1H), 5.67 (dd, J=10.0, 4.4 Hz, 1H), 5.14 (s, 2H), 4.41 (d, J=6.7 Hz,1H), 3.91 (s, 3H).

tert-Butyl(S)-(2-methoxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate

To a solution of benzyl(S)-(2-methoxy-8-oxo-8,9-dihydro-7H-pyrido[2,3-b]azepin-7-yl)carbamate(341 mg, 1 mmol) in MeOH were added 10% palladium on carbon (110 mg) anddi-tert-butyl carbonate (537 mg, 2 mmol). The reaction was hydrogenatedunder 50 PSI hydrogen pressure in Parr-Shaker for 15 hours. Reactionsolution was filtered through Celite and washed with MeOH. All solventswere removed under the reduced pressure. Residue obtained was purifiedby silica gel chromatography using a gradient of 0 to 40% ethyl acetatein hexane to afford tert-butyl(S)-(2-methoxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate(151 mg, 49%) as a white solid. MS (ESI, m/z) Calculated 307.1532; Found[M+1-Boc]⁺ 208.0. ¹H NMR (400 MHz, Chloroform-d) δ (ppm) 7.82 (s, 1H),7.41 (d, J=8.2 Hz, 1H), 6.50 (d, J=8.2 Hz, 1H), 5.53 (d, J=7.5 Hz, 1H),4.29 (dt, J=11.5, 7.2 Hz, 1H), 3.85 (s, 3H), 2.87-2.73 (m, 1H),2.73-2.55 (m, 2H), 2.02-1.89 (m, 1H), 1.39 (s, 9H).

tert-Butyl(S)-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate

To a solution of tert-butyl(S)-(2-methoxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (150 mg, 0.489 mmol) in anhydrous DMF (4 mL) was added methyliodide (69.3 mg, 30.4 uL, 0.489 mmol) followed by cesium carbonate (159mg, 0.489 mmol). The resulting solution was stirred at ambienttemperature for 2 days. Reaction solution was diluted with ethyl acetate(150 mL), washed with water, brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated under the reduced pressure. Residueobtained was purified by silica gel chromatography using a gradient of 0to 30% ethyl acetate in hexane to afford tert-butyl(S)-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-SH-pyrido[2,3-b]azepin-7-yl)carbamate (147 mg, 94%) as a white solid. MS (ESI, m/z) Calculated321.1689; Found [M+1-Boc]⁺ 222.0. ¹H NMR (400 MHz, Chloroform-d) δ (ppm)7.40 (d, J=8.1 Hz, 1H), 6.53 (d, J=8.2 Hz, 1H), 5.53 (d, J=7.7 Hz, 1H),4.26 (dt, J=11.2, 7.4 Hz, 1H), 3.89 (s, 3H), 3.45 (s, 3H), 2.77-2.56 (m,2H), 2.52 (dd, J=12.3, 6.4 Hz, 1H), 2.02-1.84 (m, 1H), 1.40 (s, 9H).

(S)-7-Amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one

To a solution of tert-butyl(S)-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)carbamate (35 mg, 0.11 mmol) in anhydrous dichloromethane (1 mL) wasadded trifluoracetic acid (0.1 mL). The resulting solution was stirredat ambient temperature for 3 hours. Then anhydrous 1,2-dichloroethane (1mL) was added. All solvents were removed under the reduced pressure toafford crude trifluoracetic acid salt of(S)-7-amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one.Residue obtained was used directly in next step. MS (ESI, m/z)Calculated 221.1164; Found [M+1]⁺ 222.1.

(S)—N-(2-Methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide

To a solution of crude trifluoracetic acid salt of(S)-7-amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one(0.11 mmol) and 4-phenoxypicolinic acid (28 mg, 0.13 mmol) in anhydrousDMF (1 mL) was added diisopropylethylamine (56 mg, 75 uL, 0.43 mmol)followed by HATU (49.4 mg, 0.13 mmol). The resulting solution wasstirred at ambient temperature for 19 hours. A drop of water was addedto quench the reaction. The solution was directly purified by reverseHPLC (30 to 70% acetonitrile in water with 0.1% formic acid). Desiredfractions were combined, diluted with ethyl acetate, washed withsaturated sodium bicarbonate aqueous solution, brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under thereduced pressure to afford(S)—N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (43 mg, 95%) as a white solid. MS (ESI, m/z) Calculated418.1641; Found [M+1]⁺ 419.1. ¹H NMR (400 MHz, Chloroform-d) δ (ppm)8.90 (d, J=7.6 Hz, 1H), 8.43 (dd, J=5.6, 0.5 Hz, 1H), 7.62 (dd, J=2.5,0.5 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.44-7.37 (m, 2H), 7.26-7.20 (m,1H), 7.10-7.04 (m, 2H), 6.93 (dd, J=5.6, 2.6 Hz, 1H), 6.57 (d, J=8.2 Hz,1H), 4.66 (dt, J=11.4, 7.5 Hz, 1H), 3.90 (s, 3H), 3.48 (s, 3H),2.83-2.69 (m, 2H), 2.64-2.52 (m, 1H), 2.15-2.02 (m, 1H).

(S)—N-(2-Hydroxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide

To a solution of(S)—N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (29 mg, 0.069 mmol) in anhydrous acetonitrile (1 mL) wasadded phosphorus tribromide (56 mg, 20 uL, 0.21 mmol). The resultingsolution was heated at 80° C. for 3 hours. Reaction solution was cooledto ambient temperature and methanol was added carefully to quench thereaction. All solvents were removed under the reduced pressure. Crudesolid was dissolved in DMSO and purified by reverse HPLC (20 to 56%acetonitrile in water with 0.1% formic acid). Desired fractions werecombined and lyophilized to afford(S)—N-(2-hydroxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (24 mg, 87%) as a white solid. MS (ESI, m/z) Calculated404.1485; Found [M+1]⁺ 405.1.

(S)-9-Methyl-8-oxo-7-(4-phenoxypicolinamido)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yltrifluoromethanesulfonate

To a solution of(S)—N-(2-hydroxy-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide (24.2 mg, 0.06 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (25.6 mg, 0.072 mmol) in anhydrous DMF (1mL) was added anhydrous potassium carbonate (17.4 mg, 0.126 mmol). Theresulting solution was stirred at ambient temperature for 20 hours.Reaction solution was diluted with ethyl acetate, washed with water,brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under the reduced pressure. Residue obtained was purifiedby silica gel chromatography using a gradient of 0 to 50% ethyl acetatein hexane to afford(S)-9-methyl-8-oxo-7-(4-phenoxypicolinamido)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yltrifluoromethanesulfonate (30 mg, 92%) as a white solid. MS (ESI, m/z)Calculated 536.0977; Found [M+1]⁺ 537.0.

General Procedure to Prepare 7-Ethynyl Pyridoazepine Compound XI

(S)-9-methyl-8-oxo-7-(4-phenoxypicolinamido)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yltrifluoromethanesulfonate (0.03 mmol, 1 eq), substituted ethyne (0.06 to0.09 mmol, 2 to 3 eq), Pd(PPh₃)₄(0.01 mmol, 0.1 eq) and CuI (0.01 mmol,0.1 eq) in anhydrous DMF (0.5 mL) in a vial was added Et₃N (0.4 mmol, 4eq). The reaction solution was purged with nitrogen for 1 minute, thensealed and heated at 70° C. for 14 to 24 hours. Reaction solution wascooled to ambient temperature, diluted with ethyl acetate (100 mL),washed with brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under the reduced pressure. Residue obtained was purifiedby silica gel chromatography or reverse HPLC (mobile phase A: water with0.1% HCOOH; mobile phase B: acetonitrile with 0.1% HCOOH) to affordintermediate final product XI. Compounds I-52, I-53, I-54, I-55, I-56,I-57, I-58, I-59 and I-60 are exemplary compounds synthesized by thisgeneral method. The picolinamide ring (the ‘B’ ring according toformulas presented herein) may be replaced with other heteroaryl groupsin the general synthesis of XI presented above, as will be readilyappreciated by those of skill in the art. For example, the picolinamidemoiety may be replaced by another 5 or 6-membered heteroaryl ringdescribed herein. By way of example of such a replacement, compound I-54contains a triazole in the ‘B’ ring position. The general synthesispresented above was adapted according to the following working example.

Synthesis of(S)-5-benzyl-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide(I-54)

Step 1(S)-5-Benzyl-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of crude trifluoracetic acid salt of(S)-7-amino-2-methoxy-9-methyl-5,6,7,9-tetrahydro-8H-pyridol[2,3-b]azepin-8-one(0.0523 mmol) and 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (10.6 mg,0.0523 mmol) in anhydrous DMF (0.5 mL) was added diisopropylethylamine(27 mg, 37 uL, 0.209 mmol) followed by HATU (21.9 mg, 0.0575 mmol). Theresulting solution was stirred at ambient temperature for 19 hours. Adrop of water was added to quench the reaction. The solution wasdirectly purified by reverse HPLC (15 to 52% acetonitrile in water with0.1% formic acid). Desired fractions were combined, and lyophilized toafford(S)-5-benzyl-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide(21 mg, 97%) as a white solid. MS (ESI, m/z) Calculated 406.1753; Found[M+1]⁺ 407.1.

Step 2(S)-5-Benzyl-N-(2-hydroxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of(S)-5-benzyl-N-(2-methoxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide(21 mg, 0.051 mmol) in anhydrous acetonitrile (1 mL) was addedphosphorus tribromide (41 mg, 14 uL, 0.15 mmol). The resulting solutionwas heated at 80° C. for 3 hours. Reaction solution was cooled toambient temperature and methanol was added carefully to quench thereaction. All solvents were removed under the reduced pressure. Crudesolid was dissolved in DMSO and purified by reverse HPLC (10 to 40%acetonitrile in water with 0.1% formic acid). Desired fractions werecombined and lyophilized to afford(S)-5-benzyl-N-(2-hydroxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide(18 mg, 91%) as a white solid. MS (ESI, m/z) Calculated 392.1597; Found[M+1]⁺ 393.1.

Step 3(S)-7-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yltrifluoromethanesulfonate

To a solution of(S)-5-benzyl-N-(2-hydroxy-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide(18 mg, 0.046 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (19.7 mg, 0.055 mmol) in anhydrous DMF (1mL) was added anhydrous potassium carbonate (15.2 mg, 0.11 mmol). Theresulting solution was stirred at ambient temperature for 2 hours.Reaction solution was diluted with ethyl acetate, washed with water,brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under the reduced pressure. Residue obtained was purifiedby silica gel chromatography using a gradient of 0 to 50% acetone inhexane to afford(S)-7-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yltrifluoromethanesulfonate (22 mg, 92%) as a white solid. MS (ESI, m/z)Calculated 524.1090; Found [M+1]⁺ 525.0.

Step 4(S)-5-benzyl-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide

(S)-7-(5-Benzyl-1H-1,2,4-triazole-3-carboxamido)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yltrifluoromethanesulfonate (22 mg, 0.0422 mmol), 2-methylbut-3-yn-2-ol(11.6 mg, 0.0138 mmol), Pd(PPh₃)₄(5.3 mg, 0.0046 mmol) and CuI (0.9 mg,0.0046 mmol) in anhydrous DMF (1 mL) in a vial was added Et₃N (18.6 mg,26 uL, 0.184 mmol). The reaction solution was purged with nitrogen for 1minute, then sealed and heated at 70° C. for 14 hours. Reaction solutionwas cooled to ambient temperature, diluted with ethyl acetate, washedwith brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under the reduced pressure. Residue obtained was purifiedby reverse HPLC (15% to 47% acetonitrile in water with 0.1% formicacid). Desired fractions were combined, diluted with ethyl acetate,washed with a little saturated sodium bicarbonate, brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under thereduced pressure to afford(S)-5-benzyl-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-1,2,4-triazole-3-carboxamide(4.0 mg, 21%) as a white solid. MS (ESI, m/z) Calculated 458.2066; Found[M+1]⁺ 459.1. ¹H NMR (400 MHz, Chloroform-d) δ (ppm) 8.12 (d, J=7.2 Hz,1H), 7.53 (d, J=7.7 Hz, 1H), 7.35-7.25 (m, 5H), 7.23 (d, J=7.7 Hz, 1H),4.57 (dt, J=12.1, 6.9 Hz, 1H), 4.14 (s, 2H), 3.50 (s, 3H), 2.90-2.73 (m,2H), 2.71-2.57 (m, 1H), 2.20 (s, 1H), 2.13-2.03 (m, 1H), 1.63 (s, 6H).

(S)—N-(2-(3-Hydroxy-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide(I-52)

MS (ESI, m/z) Calculated 470.1954; Found [M+1]⁺ 471.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.93 (d, J=7.3 Hz, 1H), 8.43 (dd, J=5.6, 0.5 Hz,1H), 7.62 (dd, J=2.6, 0.5 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.45-7.36 (m,2H), 7.26-7.21 (m, 2H), 7.11-7.03 (m, 2H), 6.93 (dd, J=5.6, 2.6 Hz, 1H),4.59 (dt, J=11.1, 7.2 Hz, 1H), 3.52 (s, 3H), 2.93-2.73 (m, 2H),2.73-2.58 (m, 1H), 2.14 (s, 1H), 2.13-1.99 (m, 1H), 1.65 (s, 6H).

(S)—N-(2-((3-Hydroxyoxetan-3-yl)ethynyl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide(I-53)

MS (ESI, m/z) Calculated 484.1747; Found [M+1]⁺ 485.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.94 (d, J=7.3 Hz, 1H), 8.44 (dd, J=5.6, 0.6 Hz,1H), 7.62 (dd, J=2.6, 0.5 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.45-7.37 (m,2H), 7.30 (d, J=7.6 Hz, 1H), 7.26-7.20 (m, 1H), 7.11-7.04 (m, 2H), 6.93(dd, J=5.6, 2.5 Hz, 1H), 4.98 (dd, J=6.6, 1.0 Hz, 2H), 4.80 (dt, J=6.8,0.7 Hz, 2H), 4.61 (dt, J=11.1, 7.3 Hz, 1H), 3.52 (s, 3H), 2.89 (s, 1H),2.88-2.75 (m, 2H), 2.75-2.62 (m, 1H), 2.18-2.04 (m, 1H).

N-((7S)-9-Methyl-8-oxo-2-(4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide(I-55)

MS (ESI, m/z) Calculated 510.1515; Found [M+1]⁺ 511.0. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 9.01 (dd, J=20.7, 7.2 Hz, 1H), 8.42 (dd, J=5.6,1.2 Hz, 1H), 7.63-7.53 (m, 2H), 7.45-7.35 (m, 2H), 7.31-7.25 (m, 1H),7.24-7.18 (m, 1H), 7.09-7.00 (m, 2H), 6.92 (dd, J=5.6, 2.5 Hz, 1H), 4.91(d, J=6.4 Hz, 1H), 4.80-4.52 (m, 1H), 3.97-3.77 (m, 0.5H), 3.66-3.52 (m,0.5H), 3.52-3.34 (m, 3H), 2.97-2.76 (m, 2H), 2.76-2.59 (m, 1H),2.19-2.00 (m, 1H).

N-((7S)-9-Methyl-8-oxo-2-(4,4,4-trifluoro-3-hydroxy-3-methylbut-1-yn-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide(I-56)

MS (ESI, m/z) Calculated 524.1671; Found [M+1]⁺ 525.2. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.97 (dd, J=12.6, 7.2 Hz, 1H), 8.43 (d, J=5.6 Hz,1H), 7.64-7.54 (m, 2H), 7.46-7.35 (m, 2H), 7.32-7.18 (m, 2H), 7.10-7.01(m, 2H), 6.96-6.87 (m, 1H), 4.64 (ddt, J=20.4, 11.3, 7.1 Hz, 1H),3.55-3.39 (m, 3.5H), 3.23 (s, 0.5H), 2.93-2.76 (m, 2H), 2.75-2.63 (m,1H), 2.19-1.98 (m, 1H), 1.74 (s, 3H).

(S)—N-(2-((3,3-Difluoro-1-hydroxycyclobutyl)ethynyl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide(I-57)

MS (ESI, m/z) Calculated 518.1766; Found [M+1]⁺ 519.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.95 (d, J=7.3 Hz, 1H), 8.43 (dd, J=5.6, 0.6 Hz,1H), 7.62 (dd, J=2.6, 0.5 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.45-7.37 (m,2H), 7.27 (d, J=5.2 Hz, 1H), 7.26-7.21 (m, 1H), 7.10-7.04 (m, 2H), 6.93(dd, J=5.6, 2.5 Hz, 1H), 4.61 (dt, J=11.1, 7.1 Hz, 1H), 3.52 (s, 3H),3.29-3.14 (m, 2H), 3.07-2.92 (m, 2H), 2.84 (dtd, J=15.2, 7.5, 5.6 Hz,2H), 2.75-2.59 (m, 1H), 2.19-2.03 (m, 1H).

(S)—N-(9-Methyl-2-(oxetan-3-ylethynyl)-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide(I-58)

MS (ESI, m/z) Calculated 468.1798; Found [M+1]⁺ 469.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.94 (d, J=7.3 Hz, 1H), 8.43 (dd, J=5.6, 0.5 Hz,1H), 7.62 (dd, J=2.5, 0.5 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.45-7.35 (m,2H), 7.27-7.22 (m, 3H), 7.10-7.04 (m, 2H), 6.93 (dd, J=5.6, 2.6 Hz, 1H),4.92-4.79 (m, 4H), 4.60 (dt, J=11.2, 7.3 Hz, 1H), 4.12 (tt, J=8.5, 7.4Hz, 1H), 3.52 (s, 3H), 2.94-2.73 (m, 2H), 2.73-2.61 (m, 1H), 2.19-2.03(m, 1H).

(S)—N-(2-(3,3-Difluoro-3-(oxetan-3-yl)prop-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide(I-59

MS (ESI, m/z) Calculated 518.1766; Found [M+1]⁺ 519.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.93 (d, J=7.3 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H),7.65-7.59 (m, 2H), 7.45-7.35 (m, 3H), 7.26-7.20 (m, 1H), 7.10-7.04 (m,2H), 6.94 (dd, J=5.6, 2.5 Hz, 1H), 4.90-4.74 (m, 4H), 4.59 (dt, J=11.3,7.2 Hz, 1H), 3.83-3.62 (m, 1H), 3.53 (s, 3H), 2.96-2.76 (m, 2H), 2.72(dd, J=11.9, 6.2 Hz, 1H), 2.20-2.06 (m, 1H).

N-((7S)-2-(3-Amino-4,4,4-trifluoro-3-methylbut-1-yn-1-yl)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-phenoxypicolinamide(I-60)

MS (ESI, m/z) Calculated 523.1831; Found [M+1]⁺ 524.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.93 (d, J=7.3 Hz, 1H), 8.43 (dd, J=5.6, 0.6 Hz,1H), 7.62 (dd, J=2.6, 0.5 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.44-7.37 (m,2H), 7.30-7.21 (m, 2H), 7.09-7.04 (m, 2H), 6.93 (dd, J=5.6, 2.5 Hz, 1H),4.58 (dt, J=11.1, 7.2 Hz, 1H), 3.52 (s, 3H), 2.93-2.75 (m, 2H),2.75-2.63 (m, 1H), 2.17-2.02 (m, 1H), 2.02-1.81 (m, 2H), 1.67 (d, J=0.9Hz, 3H).

(S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(I-1)

¹H NMR (400 MHz, CD₂Cl₂) δ 8.30 (dd, J=4.7, 1.6 Hz, 1H), 8.06 (d, J=7.0Hz, 1H), 7.53 (dd, J=8.0, 1.6 Hz, 1H), 7.32-7.21 (m, 5H), 7.18 (dd,J=8.0, 4.7 Hz, 1H), 4.99 (dt, J=11.3, 7.0 Hz, 1H), 4.76 (dd, J=9.8, 7.1Hz, 1H), 4.32 (dd, J=11.3, 9.8 Hz, 1H), 4.17 (d, J=2.1 Hz, 2H), 3.49 (s,3H). HRMS (TOFMS ES+) exact mass C₁₉H₁₈N₆O₃ 378.1440, found 379.1566.

(S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide(I-2)

MS (ESI, m/e) Calculated 379.1281; Found 380.0 [M+H]⁺.

(S)-5-Benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(I-3)

MS (ESI, m/e) Calculated 460.1859; Found 443.1 [M−H₂O+H]⁺.

(S)-5-Benzyl-N-(5-methyl-8-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide(I-5)

MS (ESI, m/e) Calculated 502.1965; Found 503.1 [M+H]⁺.

Synthesis of(S)-3-Amino-8-bromo-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-oneHydrochloride (I-6)

The 8-bromo compound illustrated in the scheme above as structure 4 iscompound I-6 of the present disclosure. Compound 1-6, in addition toexhibiting RIP1K inhibitory activity, is useful as an intermediate forsynthesizing 8-substituted pyridoxazepines. For example, compound I-6can be cross-coupled, for example under palladium catalyzed conditionswith amino moieties as well as unsaturated groups as is known to thoseof skill in the art.

Hydrogen chloride solution (1 mL, 4M in dioxane, 4 mmol) was added to avial containing tert-butyl(S)-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate1 (prepared as described in WO2020239074, 52 mg, 0.139 mmol). Theresulting solution was stirred at ambient temperature for 19 hrs. Allsolvents were removed under reduced pressure to afford(S)-3-amino-8-bromo-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride 2 (43 mg, 100%) as a white solid. MS (ESI, m/e) Calculated270.9956; Found 272.0 [M+H]⁺.

Synthesis of(S)—N-(8-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(4)

To a solution of(S)-3-amino-8-bromo-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride 2 (43 mg, 86 μmol) and 4-phenoxypicolinic acid 3 (45 mg,0.21 mmol) in anhydrous DMF (1.4 mL) was added diisopropylethylamine(135 mg, 0.18 mL, 1.1 mmol) followed by HATU (80 mg, 0.21 mmol). Theresulting solution was stirred at ambient temperature for 16 hrs. Water(0.1 mL) was then added, and the solution was directly purified byreverse HPLC using a gradient of 37 to 90% acetonitrile in waterbuffered with 0.1% formic acid. The desired fractions were combined,diluted with ethyl acetate (100 mL) and the resulting solution waswashed with saturated sodium bicarbonate solution, brine, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to afford(S)—N-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide4 (50 mg, 77%) as a white solid. MS (ESI, m/e) Calculated 468.0433;Found 468.9 [M+H]⁺.

(S)—N-(8-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-6)

MS (ESI, m/e) Calculated 468.0433; Found 468.9 [M+H]⁺. (I-6)

(S)—N-(8-(3-Hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-7)

MS (ESI, m/e) Calculated 472.1747; Found 473.1 [M+H]⁺.

(S)—N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-18)

MS (ESI, m/z) Calculated 472.1747; Found [M+1]⁺ 473.1. ¹H NMR (400 MHz,Methanol-d₄) δ (ppm) 8.52 (dd, J=5.7, 0.5 Hz, 1H), 7.61 (d, J=8.1 Hz,1H), 7.52-7.44 (m, 3H), 7.36 (d, J=8.2 Hz, 1H), 7.34-7.27 (m, 1H),7.17-7.12 (m, 2H), 7.09 (dd, J=5.6, 2.6 Hz, 1H), 5.00 (dd, J=11.5, 7.0Hz, 1H), 4.69 (dd, J=9.8, 7.0 Hz, 1H), 4.49 (dd, J=11.5, 9.8 Hz, 1H),3.46 (s, 3H), 1.57 (s, 6H).

(S)—N-(7-((3,3-difluoro-1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-30)

MS (ESI, m/z) Calculated 520.1558; Found [M+1]⁺ 521.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.97 (d, J=6.9 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H),7.61 (d, J=2.5 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.46-7.39 (m, 2H), 7.29(d, J=8.1 Hz, 1H), 7.24 (t, J=1.2 Hz, 1H), 7.11-7.04 (m, 2H), 6.96 (dd,J=5.6, 2.5 Hz, 1H), 5.09 (dt, J=11.4, 6.8 Hz, 1H), 4.81 (dd, J=9.7, 6.8Hz, 1H), 4.36 (dd, J=11.4, 9.7 Hz, 1H), 3.50 (s, 3H), 3.22 (tdd, J=11.9,9.3, 3.7 Hz, 2H), 3.08-2.86 (m, 3H).

(S)—N-(7-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-31)

MS (ESI, m/z) Calculated 486.1903; Found [M+1]⁺ 487.1. ¹H NMR (400 MHz,Chloroform-d) δ (ppm) 8.92 (d, J=7.0 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H),7.61 (d, J=2.5 Hz, 1H), 7.47-7.37 (m, 3H), 7.28 (d, J=1.1 Hz, 1H), 7.25(d, J=5.9 Hz, 1H), 7.10-7.04 (m, 2H), 6.96 (dd, J=5.6, 2.5 Hz, 1H), 5.00(dt, J=11.4, 7.0 Hz, 1H), 4.78 (dd, J=9.7, 7.0 Hz, 1H), 4.34 (dd,J=11.4, 9.7 Hz, 1H), 3.54 (s, 2H), 3.53 (s, 3H), 1.34 (s, 6H).

(S)—N-(7-(4-Hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-31)

¹H NMR (400 MHz, CD₂Cl₂) δ 8.74 (d, J=7.2 Hz, 1H), 8.47 (dd, J=5.6, 0.5Hz, 1H), 7.56 (dd, J=2.6, 0.5 Hz, 1H), 7.49-7.40 (m, 2H), 7.31-7.25 (m,3H), 7.14-7.08 (m, 3H), 6.98 (dd, J=5.6, 2.6 Hz, 1H), 4.97 (dt, J=11.2,7.3 Hz, 1H), 4.69 (dd, J=9.7, 7.3 Hz, 1H), 4.25 (dd, J=11.3, 9.7 Hz,1H), 3.48 (s, 2H), 3.40 (s, 3H), 1.87 (s, 1H), 1.29 (s, 6H). HRMS (TOFMSES+) exact mass C₂₈H27N₃O₅ 485.1951, found 486.2024.

(S)—N-(8-(4-Hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-8)

¹H NMR (400 MHz, CDCl₃) δ 8.91 (d, J=7.0 Hz, 1H), 8.44 (d, J=5.6 Hz,1H), 8.30 (d, J=1.9 Hz, 1H), 7.62 (d, J=2.5 Hz, 1H), 7.51 (d, J=2.0 Hz,1H), 7.41 (td, J=8.9, 7.2 Hz, 2H), 7.27-7.24 (m, 1H), 7.12-7.03 (m, 2H),6.95 (dd, J=5.6, 2.5 Hz, 1H), 5.00 (dt, J=11.4, 7.0 Hz, 1H), 4.76 (dd,J=9.7, 7.0 Hz, 1H), 4.34 (dd, J=11.4, 9.7 Hz, 1H), 3.54 (s, 2H), 3.51(s, 3H), 1.91 (s, 1H), 1.33 (s, 6H). HRMS (TOFMS ES+) exact massC₂₇H₂₆N₄O₅ 486.1903, found 487.1988.

(S)—N-(5-Methyl-4-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide(I-9)

HRMS (TOFMS ES+) exact mass C₂₈H₂₁N₅O₄ 491.1594, found 492.1680.

Kinase Inhibition

In this example, compounds of the disclosure were evaluated using abiochemical assay using the ADP-Glo™ technology.

ADP-Glo™ (Promega, Madison, Wis., USA) reagents were thawed at ambienttemperature. Kinase Detection Reagent was prepared by mixing kinasedetection buffer with the lyophilized kinase detection substrate.

A 500 ml stock volume of 5× Reaction Kinase Buffer was made by mixing1000 μl of 1M MgCl₂, 500 μl of 1M Tris-HCL pH7.4, 0.5 mg/ml (25 mg) ofBSA, and 3475 μl of distilled H₂O. A 3 ml 2× working stock volume ofReaction Kinase Buffer was made containing a final concentration of 100μM DTT and 4 mM MnCl₂.

Components of RIPK1 enzyme (Rigel Pharmaceuticals, South San Francisco,Calif., USA) were thawed on ice. Diluted RIPK1 was prepared in 1× KinaseReaction Buffer (diluted from 2× buffer) to 31 ng/well. A 166 M workingstock ATP assay solution was prepared in 1× Kinase Reaction Buffer(diluted from 2× buffer).

Compounds were serially diluted in DMSO from 250 uM in 4-fold dilutionsthen diluted 1:5 in 2× Reaction Buffer in a 96 well plate. 1.0 ul ofdiluted compound was added to a 384 well plate in duplicate. 2 μl ofdiluted Active RIPK1 was added to 384 well plate (do not add tocolumn 1) add 2× r×n buffer to column 1. AKT (Anaspec, Fremont, Calif.,USA) at 150 nM was combined with ATP working stock at equal volume and 2ul/well were added to the 384 well plate. The final reaction volume was5.0 μl.

The plate was quickly centrifuged and the reaction was incubated at 30°C. for 30 minutes. Adding 5 μl of ADP-Glo™ terminated the reaction. Theplate was quickly centrifuged and the reaction was incubated at roomtemperature for 40 minutes. Kinase Detection Reagent was then added andincubated at room temperature for 30 minutes. The relative light unit(RLU) of kinase reaction was determined by luminescent (Luminescence0.1s) using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, Mass.,USA). IC₅₀ values obtained from this example are provided by Table 1.

TABLE 1 Compound RIPK1 ADP-Glo Kinase (IC₅₀) I-1 0.0375 I-2 0.038 I-30.0627 I-4 0.0229 I-5 0.0728 I-6 0.0221 I-7 0.0693 I-8 0.034 I-9 1.845I-10 0.0538 I-11 12.03 I-12 0.1482 I-13 0.0257 I-14 3.723 I-15 0.2192I-16 6.255 I-17 0.024 I-18 0.0227 I-19 0.0162 I-20 0.0099 I-21 0.023I-22 0.0172 I-23 0.0261 I-24 0.0291 I-25 0.1104 I-26 0.0265 I-27 0.026I-28 0.0188 I-29 0.0211 I-30 0.0179 I-31 0.0196 I-32 0.0381 I-33 0.013I-34 0.0269 I-35 0.0201 I-36 0.0335 I-37 0.0377 I-38 0.0208 I-39 0.0217I-40 0.012 I-41 0.0189 I-42 0.018 I-43 0.0112 I-44 0.0116 I-45 0.0598I-46 0.0108 I-47 0.0321 I-48 0.0344 I-49 0.1097 I-50 5.058 I-51 0.0167I-52 0.0178 I-53 0.0117 I-54 0.1016 I-55 0.0135 I-56 0.0157 I-57 0.0079I-58 0.0172 I-59 0.0205 I-60 0.0085

Whole Cell Assay Data

In this example, U937 and L929 cells were exposed to compounds of thepresent disclosure and a cell necroptosis assay was conducted toevaluate the compounds' activity against human RIP1 and murine RIP1.

U937 and L929 cells were obtained from the American Type CultureCollection (Manassa, Va., USA). Both cells were maintained inlogarithmic growth phase in complete RPMI 1640 media (Sigma, ST Louis,Mo., USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis,Mo., USA) at 37° C. with 5% CO₂. For necroptosis assay, L929 cells wereplated for 18h in 100 μL/well medium at 10K cells/well in Costar 96-wellblack clear-bottom plates (Fisher Scientific, Hampton, N.H., USA); U937cells were plated on the day of the assay in 50 μL/well mediumcontaining 60 uM zVAD-fmk (Lonza, Basel, Switzerland) at 50K cells/well.Medium from L929 cells were removed from the 96-well plates and replacedwith 50 μL/well new medium containing 40 uM zVAD-fmk. Each compound ofthe present disclosure evaluated in this example was serially diluted inDMSO from 2.5 mM in 4-fold dilutions, and then diluted 1:125 in completemedium. 50 μL/well 2× of the compound was then added to the cells in theplates. The cells were pre-incubated with the compound for 1 hour at 37°C. with 5% CO₂ and before addition of 10 μL/well 11×TNFa (Peprotech,Rocky Hill, N.J., USA) to give a final concentration of 2 ng/mL forTNFa. The relative amount of necroptosis cells was determined byluminescent using a Wallac Victor2 Luminometer (PerkinElmer, Waltham,Mass., USA) and a CellTiter-Glo® Luminescent Cell Viability ReagentAssay (Promega, Madison, Wis., USA) added per manufacturer instructionsafter 18 hours of TNFa stimulation at 37° C. with 5% CO₂. Results fromthis example are summarized in Table 2. This example establishes thatembodiments of the compounds described herein have unexpectedly potentactivity against human RIP1 and murine RIP1, which allows theirassessment in in vivo mouse models of disease. These results are usefulin determining safe and effective doses for humans.

TABLE 2 L929-CTG-recovery, U937 Zvad TNF CTG Recovery, L929, TNFa + zVADU937, TNFa + zVAD Compound (IC₅₀) (IC₅₀) I-1 2.197 0.0054 I-2 1.7350.0088 I-3 0.7303 0.0114 I-4 0.5818 0.0452 I-5 0.848 0.0025 I-6 0.23230.0024 I-7 1.004 0.0022 I-8 0.5385 0.0033 I-9 14.67 0.514 I-10 0.88960.1658 I-11 9999 9999 I-12 12.65 0.0352 I-13 4.111 0.0115 I-14 9999 3.64I-15 7.396 19.19 I-16 9999 7.11 I-17 0.3923 0.0025 I-18 0.8655 0.0043I-19 0.6463 0.0166 I-20 0.7101 0.0024 I-21 2.631 0.0097 I-22 0.66880.0017 I-23 2.354 0.0023 I-24 0.6616 0.003 I-25 8.816 0.0273 I-26 0.32440.0013 I-27 9.421 0.0706 I-28 1.553 0.0067 I-29 0.626 0.0027 I-30 0.64770.001 I-31 2.197 0.0054 I-32 1.735 0.0088 I-33 0.204 0.0014 I-34 0.21580.0063 I-35 0.7077 0.0114 I-36 0.0159 0.0009 I-37 0.0318 0.0034 I-380.0066 0.0021 I-39 4.199 0.021 I-40 0.7748 0.0276 I-41 0.3381 0.0033I-42 0.9114 0.0196 I-43 0.3231 0.0036 I-44 0.0597 0.0011 I-45 0.94540.0162 I-46 0.1986 0.0027 I-47 0.0065 0.0003 I-48 3.403 0.0543 I-49 30.30.2435 I-50 67.61 6.142 I-51 5.134 0.0874 I-52 0.0475 0.0128 I-53 0.02210.0057 I-54 0.4367 0.0128 I-55 0.0755 0.0045 I-56 0.0582 0.0041 I-570.1357 0.008 I-58 0.0813 0.003 I-59 0.0582 0.0056 I-60 0.2034 0.0057

Acute In Vivo Assay

In this example, an acute hypothermia mouse model assay was used toevaluate the ability of compounds disclosed herein to inhibit TNF-alphainduced hypothermia.

Female C57BL/6 mice are randomly grouped and weighed on Day −1. On theday of the study (Day 0), mice are administered vehicle or test articleby oral gavage. Fifteen minutes after oral administration of testagents, each mouse is administered an intraperitoneal (IP) injection ofsolution containing recombinant human tumor necrosis factor alpha(TNF-a, 25.0 μg) and zVAD-FMK (200 pg). Body temperature is measured at0 hours (before IP injections) and every hour via rectal probetemperature measuring device. Three (3) hours after IP injections ofTNF-α and zVAD/FMK, mice are euthanized by CO₂ asphyxiation and blood iscollected via cardiac puncture. Serum and plasma are harvested fordetermination of cytokine and compound levels, respectively. Separategroups of mice (satellite mice) are included for the determination ofcompound levels in plasma at the time of administration ofTNFa/zVAD-FMK. Compounds of the present disclosure inhibited TNF-alphainduced hypothermia.

Brain Penetration

Certain embodiments of the invention provide for compound, compounds orcompositions thereof to traverse the blood-brain barrier. Disclosedcompound and composition embodiments exhibit sufficient brainpenetration as potential therapeutics in neurological diseases. Brainpenetration may be assessed by evaluating brain/plasma ratio (B/P) asmeasured through in vivo pharmacokinetic studies in rodents anddetermining free fraction in rodent brain in vitro. By way of examplecompound I-44 exhibited a B/P ratio of 1.6 and compound I-58 exhibited aB/P ratio of 0.44. Other examples exhibited higher partition ratios.Without being limited to theory, it is believed that compounds withhigher brain/plasma partition ratios may be more pharmacologicallyactive against neurological disorders. Other methods for assessing brainpenetration are known to persons of ordinary skill in the art. See, forexample, Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008.1I-MDR1 Permeability. In this method, the passive membrane permeability(Papp) and the P-gp (P-glycoprotein) substrate efflux potential aredetermined using a MDCKII-MDR1 cell line as an in vitro model of theeffective permeability of a compound through the BBB. Compounds with anMDCKII-MDR1 efflux ratio of less than or equal to 2.5 are likely todemonstrate ability to cross the blood-brain-barrier.

Brain free fraction is a predictive marker for assessing potential forpotential therapeutics in the CNS. See, Read K. D.; Braggio S. Assessingbrain free fraction in early drug discovery. Expert. Opin. Drug. Metab.Toxicol. 2010, 6, 337-344.

Accordingly, the brain free fraction for representative compounds isprovided in Table 3:

TABLE 3 Compound % Unbound I-18 2.7 I-21 2.19 I-33 0.57 I-44 1.70 I-460.89 I-56 0.93 I-58 1.84Determination of brain free fraction is known such that those of skillin the art could determine the brain free fraction for additionalcompounds disclosed herein. See, Srinivas, Nithya et al. “ClinicalPharmacokinetics and Pharmacodynamics of Drugs in the Central NervousSystem.” Clinical pharmacokinetics vol. 57, 9 (2018): 1059-1074.doi:10.1007/s40262-018-0632-y. The brain free fraction reported in Table3 indicates that exemplary compounds exhibit characteristics ofCNS-active compounds.

In view of the many possible embodiments to which the principles of thedisclosed invention may be applied, it should be recognized that theillustrated embodiments are only preferred examples of the invention andshould not be taken as limiting the scope of the invention. Rather, thescope of the invention is defined by the following claims. We thereforeclaim as our invention all that comes within the scope and spirit ofthese claims.

We claim:
 1. A compound according to Formula I

wherein ring B is 5-membered or 6-membered heteroaryl; X is CH₂ or O; Lis a heteroatom or R^(a), provided that R^(a) is not hydrogen; Z isC₁₋₁₀aliphatic (such as C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₆cycloalkyl); aryl or heteroaryl, each optionally substituted withone or more R⁵ group; R¹ is independently for each occurrence—NR^(d)R^(d) wherein the two R^(d) groups together with the nitrogenbound thereto provide a C₃₋₁₀heterocyclic group; —C≡CH, or a -linker-R⁶group, wherein the linker is a divalent C₁₋₁₀aliphatic moiety (such asC₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl) or C₁₋₁₀cycloaliphatic moiety,and R⁶ is R^(b), —C(R^(f))₃, or —C(R^(f))═C(R^(f))₂; C₅₋₁₀aromatic, orC₃₋₆heterocyclic, each linker optionally substituted with one or morehalo, R^(a), or both; R² and R³ independently are R^(a); R⁴ and R⁵independently are, for each occurrence, R^(e); R^(a) is independentlyfor each occurrence hydrogen, C₁₋₁₀aliphatic, C₁₋₁₀haloaliphatic,C₅₋₁₀aromatic, or C₃₋₆heterocyclic; R^(b) is independently for eachoccurrence —OH, —SH, —OR^(c), —SR^(c), —NR^(e)R^(e), —Si(R^(a))₃,—C(O)OH, —C(O)OR^(c), or —C(O)NR^(e)R^(e) R^(c) is independently foreach occurrence C₁₋₁₀alkyl (optionally substituted with 1, 2 or 3R^(e)), C₂₋₁₀alkenyl (optionally substituted with 1, 2 or 3 R^(e)),C₂₋₁₀alkynyl (optionally substituted with 1, 2 or 3 R^(e)),C₃₋₆cycloalkyl (optionally substituted with 1, 2 or 3 R^(e)), orC₅₋₁₀aromatic (optionally substituted with 1, 2 or 3 R^(e)); R^(d) isC₁₋₉aliphatic optionally substituted with 1, 2, or 3 R^(a), R^(b) and/orR^(e) groups; R^(e) is independently for each occurrence oxo (═O),—OR^(a), N(R^(a))₂, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl,C₃₋₆cycloalkyl, or two R^(e) groups join together to provide aC₃₋₁₀heterocyclic group with a nitrogen to which the two R^(e) groupsare bound; m is 1 to 4; and n is 0, 1 or
 2. 2. A method for inhibiting aRIP kinase, comprising contacting the kinase with a compound accordingto claim
 1. 3. The compound of claim 1, wherein ring B is 5-membered or6-membered heteroaryl.
 4. The compound of claim 1, wherein ring B is a5-membered heteroaryl.
 5. The compound of claim 4, wherein ring B is atriazole, a diazole, an oxazole or an oxadiazole.
 6. The compound ofclaim 1, wherein ring B is pyrazolyl, and the —N(R³)C(O)— moiety isattached to ring B at a ring nitrogen atom on ring B.
 7. The compound ofclaim 1, wherein ring B is 6-membered heteroaryl.
 8. The compound ofclaim 7, wherein ring B is pyridinyl.
 9. The compound of claim 1,wherein R² is C₁₋₆alkyl.
 10. The compound of claim 1, wherein R² ismethyl.
 11. The compound of claim 10, wherein R² is CD₃.
 12. Thecompound of claim 1, wherein R³ is H.
 13. The compound of claim 1,wherein n is
 0. 14. The compound of claim 1, wherein n is
 1. 15. Thecompound of claim 1, wherein at least one R⁴ is C₁₋₆alkyl.
 16. Thecompound of claim 1, wherein at least one R⁴ is fluoro.
 17. The compoundof claim 14, wherein R⁴ is C₁₋₆alkyl or fluoro.
 18. The compound ofclaim 1, wherein X is O.
 19. The compound of claim 1, wherein X is—CH₂—.
 20. The compound of claim 1, wherein L is a heteroatom.
 21. Thecompound of claim 13, wherein L is O.
 22. The compound of claim 1,wherein L is C₁₋₆alkyl.
 23. The compound of claim 1, having Formula II


24. The compound of claim 1, having Formula IIA


25. The compound of claim 1, having Formula IIB, IIC, IID or IIE

wherein each W is independently N or O.
 26. The compound of claim 1,having Formula IIF, IIG, IIH


27. The compound of claim 1, having Formula IIK


28. The compound of claim 1, wherein m is
 1. 29. The compound of claim1, wherein at least one R¹ is halogen.
 30. The compound of claim 1,wherein at least one R¹ is -linker-R⁶.
 31. The compound of claim 29,wherein at least one R¹ is 8- to 12-membered spiroheterocyclyl,C₁₋₁₀alkyl or a C₂₋₁₀alkyne.
 32. The compound of claim 1, wherein atleast one R¹ is selected from the following:


33. The compound of claim 1, wherein at least one R¹ is


34. The compound of claim 1, wherein at least one R¹ is selected from


35. The compound of claim 1, wherein at least one R¹ is selected from


36. The compound of claim 1, having the formula


37. The compound of claim 1, having the formula


38. A method for treating a disease in a subject, comprisingadministering to the subject (i) a therapeutically effective amount ofthe compound according to claim 1 or (ii) a therapeutically effectiveamount of a pharmaceutical composition of the compound; wherein thesubject has, or is suspected of having or developing, the disease,wherein the disease is a disease involving a receptor-interactingprotein-1 (RIP1) kinase.
 39. The method according to claim 38, whereinthe disease is an inflammatory or immune-regulatory disorder.
 40. Themethod according to claim 38, wherein the disease is an aging disorder.41. The method according to claim 38, wherein the disease is selectedfrom amyotrophic lateral sclerosis (ALS), an autoimmune syndrome,rheumatoid arthritis, type I diabetes mellitus, inflammatory boweldiseases, including Crohn's disease and ulcerative colitis, biliarycirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis,asthma, pollen allergies, reversible obstructive airway disease,bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma,dust asthma, chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, allergic rhinitis, spondyloarthritis, ankylosingspondylitis, autoimmune hepatitis, autoimmune hepatobiliary diseases,cerebrovascular accident, allergic diseases, chronic obstructivepulmonary disease, pulmonary emphysema, Friedreich's ataxia, Lewy bodydisease, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahrdisease, Menke's disease, Wilson's disease, prion disorder, destructivebone disorders such as bone resorption disease, multiple myeloma-relatedbone disorder; benign tumor, proliferative disorders, inflammatory andhyperproliferative skin disorders, an epidermal hyperproliferation,psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis,seborrhoeic dermatitis, pustular psoriasis, bullous dermatitis,dermatitis erythema multiforme, linear IgA bullous dermatitis, cementdermatitis, gingivitis, periodontitis, lesions of gingiva, alveolarbone, substantia ossea dentis, sepsis, pancreatitis, lichen planus,pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, adiposis,eosinophilic fascitis, acne, alopecia areata, male pattern alopecia,alopecia senilis, keratoconjunctivitis, vernal conjunctivitis, cornealalkali burn, Behcet's disease, uveitis associated with Behcet's disease,keratitis, herpetic keratitis, conical cornea, dystrophia epithelialiscorneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis,Vogt-Koyanagi-Harada syndrome, hematological disorders, hematologicalmalignancies, lymphomas, Hodgkins lymphoma, non-Hodgkins lymphoma,mammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, ABC diffuse large B-celllymphoma (DLBCL), Waldenström's macroglobulinemia, primary cutaneousT-cell lymphoma, smoldering or indolent multiple myeloma, leukemia,acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL),chronic lymphocytic lymphoma, chronic myeloid leukemia (CML), primaryeffusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocyticleukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma,myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera,chronic myelomonocytic leukemia, Kaposi's sarcoma, splenic marginal zonelymphoma, multiple myeloma, plasmacytoma, intravascular large B-celllymphoma, IL-1 driven disorders, MyD88 driven disorders, drug resistantmalignancies, such as JAK inhibitor-resistant malignancies and ibrutinibresistant malignancies, for example ibrutinib resistant hematologicalmalignancies, ibrutinib resistant CLL and ibrutinib resistantWaldenström's macroglobulinemia, acute myelogenous leukemia, chronicmyelogenous leukemia; angiogenic disorders such as angiogenic disordersincluding solid tumors, ocular neovascularization, hemangiomas, such asinfantile hemangiomas; sepsis, septic shock, shigellosis; migraine,bronchitis, gastric ulcers, necrotizing enterocolitis, intestinallesions associated with thermal burns, celiac diseases, proctitis,eosinophilic gastroenteritis, mastocytosis, interleukin-1 convertingenzyme-associated associated fever syndrome, tumor necrosis factorreceptor-associated periodic syndrome, NEMO-deficiency syndrome, HOIL-1deficiency, linear ubiquitin chain assembly complex deficiency syndrome,a lysosomal storage disease, Gaucher disease, GM2 gangliosidosis,alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storagedisease, chronic hexosaminidase A deficiency, cystinosis, Danon disease,Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1gangliosidosis, mucolipidosis, infantile free sialic acid storagedisease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomalacid lipase deficiency, metachromatic leukodystrophy,mucopolysaccharidoses disorders, multiple sulfatase deficiency,Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease,pycnodysostosis, Sandhoff disease, Schindler disease, sialic acidstorage disease, Tay-Sachs disease, Wolman disease, Huntington'sdisease, Parkinson's disease, neurodegenerative diseases, Huntington'sdisease, Parkinson's disease, metastatic melanoma, neurodegenerationassociated with HIV infection and CMV retinitis, such as associatedneurocognitive disorders or dementia, fibrotic conditions such as,nonalcoholic steatohepatitis and cardiac conditions such as, ischemiareperfusion; allergies, adult respiratory distress syndrome, chronicobstructive pulmonary disease, glomerulonephritis, erythematosis,chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmuneneutropenia, thrombocytopenia, graft versus host disease, inflammatoryreaction induced by endotoxin, tuberculosis, atherosclerosis, muscledegeneration, cachexia, Reiter's syndrome, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis,psoriatic arthritis, and other arthritic conditions, cerebral malaria,chronic pulmonary inflammatory disease, silicosis, pulmonarysarcoidosis, fibroid lung, idiopathic interstitial pneumonia, allograftrejection, bone marrow rejection, fever and myalgias due to infection,keloid formation, scar tissue formation, pyresis, influenza, chronicmyelogenous leukemia; angiogenic disorders including solid tumors; viraldiseases including acute hepatitis infection (including hepatitis A,hepatitis B and hepatitis C), AIDS, ARC or malignancy, herpes; stroke,myocardial infarction, arteriosclerosis, atherosclerosis, aortitissyndrome, polyarteritis nodosa, myocardial ischemia, ischemia in strokeheart attacks, organ hypoxia, vascular hyperplasia, cardiac and renalreperfusion injury, ischemia-reperfusion injury of organs which occursupon preservation, transplantation or ischemic disease, cardiachypertrophy, thrombin-induced platelet aggregation, endotoxemia and/ortoxic shock syndrome, conditions associated with prostaglandinendoperoxidase syndase-2, pemphigus vulgaris, autoimmune/multiplemyositis, dermatomyositis, leukoderma vulgaris, photoallergicsensitivity, ischemia reperfusion injury, cardiac ischemia reperfusioninjury arising from myocardial infarction, multiple system atrophy,Parkinson-plus syndromes, frontotemporal dementia, intracranialhemorrhage, cerebral hemorrhage, progressive muscular atrophy,pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy,inherited muscular atrophy, peripheral neuropathies, progressivesupranuclear palsy, corticobasal degeneration, demyelinating diseases,systemic onset juvenile idiopathic arthritis (SoJIA) or Still's disease,systemic lupus erythematosus (SLE), Sjögren's syndrome,anti-phospholipid syndrome (APS), primary sclerosing cholangitis (PSC),renal transplant, surgery, acute kidney injury (AKI), systemicinflammatory response syndrome (SIRS), cytokine release syndrome (CRS),acute respiratory distress syndrome (ARDS), ARDS resulting fromCOVID-19, postinfectious autoimmune diseases, rheumatic fever,post-infectious glomerulonephritis, systemic sclerosis, cerebrovascularaccident (CVA), chronic obstructive pulmonary disease (COPD),NEMO-deficiency syndrome (F-kappa-B essential modulator gene (also knownas IKK gamma or IKKG) deficiency syndrome), solid organ malignancies,lysosomal storage diseases, glaucoma, retinal degenerative disease,retinal ischemia/reperfusion injury, renal ischemia reperfusion injury,cataracta, siderosis, retinitis pigmentosa, retinal degeneration,retinal detachment, senile macular degeneration, vitreal scarring,anthrax lethal toxin induced septic shock, cell death induced by LPS,infectious encephalopathy, encephalitis, allergic encephalomyelitis,autoimmune uveoretinitis, giant cell arteritis, regional enteritis,granulomatous enteritis, distal ileitis, regional ileitis, terminalileitis, insulin-dependent diabetes mellitus, scleroderma, systemicscleroderma, macular edema, diabetic retinopathy, central areolarchoroidal dystrophy, BEST disease, adult vitelliform disease, patterndystrophy, myopic degeneration, central serous retinopathy, Stargardt'sdisease, Cone-Rod dystrophy, North Carolina dystrophy, infectiousretinitis, inflammatory retinitis, uveitis, posterior uveitis, toxicretinitis and light-induced toxicity, macular edema, central areolarchoroidal dystrophy, BEST disease, adult vitelliform disease, patterndystrophy, optic nerve injury, optic neuritis, optic neuropathies,central retinal artery occlusion, ischemic optic neuropathy, arteriticor non-arteritic anterior ischemic neuropathy and posterior ischemicoptic neuropathy, compressive optic neuropathy, infiltrative opticneuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy,Leber's optic neuropathy, nutritional optic neuropathy, toxic opticneuropathy and hereditary optic neuropathy, Dominant Optic Atrophy,Behr's syndrome, Creutzfeldt-Jakob disease, progressive supranuclearpalsy, hereditary spastic paresis, subarachnoid hemorrhage, perinatalbrain injury, subclinical brain injury, spinal cord injury,anoxic-ischemic brain injury, cerebral ischemia, focal cerebralischemia, global cerebral ischemia, and hypoxic hypoxia, peritonealdamage caused by peritoneal dialysis fluid (PDF) and PD-related sideeffects, glomerular diseases, tubulointerstitial diseases, interstitialnephritis, obstruction, polycystic kidney disease), focalglomerulosclerosis, immune complex nephropathy, diabetic nephropathy,Goodpasture's syndrome, hepatocellular cancer, pancreatic cancer,urological cancer, bladder cancer, colorectal cancer, colon cancer,breast cancer, prostate cancer, prostate hyperplasia, renal cancer,kidney carcinoma, liver carcinoma, adrenal gland carcinoma, thyroidcancer, gall bladder cancer, peritoneal cancer, ovarian cancer, cervicalcancer, gastric cancer, endometrial cancer, esophageal cancer, stomachcancer, head and neck cancer, neuroendocrine cancer, CNS cancer, braintumors, carcinoma of the brain, glioma, anaplastic oligodendroglioma,adult glioblastoma multiforme, and adult anaplastic astrocytoma, bonecancer, soft tissue sarcoma, retinoblastomas, neuroblastomas, peritonealeffusions, malignant pleural effusions, mesotheliomas, Wilms tumors,trophoblastic neoplasms, epithelial neoplasia, stomach carcinoma,carcinoma of the ovaries, rectum carcinoma, prostate carcinoma,carcinoma of the pancreas, lung carcinoma, carcinoma of the vagina,carcinoma of the cervix, carcinoma of the testis, carcinoma of thegenitourinary tract, carcinoma of the esophagus, carcinoma of thelarynx, carcinoma of the skin, carcinoma of the bone, carcinoma of thethyroid, sarcoma, glioblastomas, neuroblastomas, gastrointestinalcancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma,large cell carcinoma, non-small-cell lung carcinoma, lymphomas, coloncarcinoma, colorectal adenoma, hemangiopericytomas, myxoid carcinoma,round cell carcinoma, squamous cell carcinomas, esophageal squamous cellcarcinomas, oral carcinomas, vulval cancer, cancers of the adrenalcortex, ACTH producing tumors, and leukemia, respiratory infectiousviruses, such as influenza virus, rhinovirus, corona virus,parainfluenza virus, RS virus, adeno virus, reo virus and the like),herpes zoster caused by herpes virus, diarrhea caused by rotavirus,viral hepatitis, AIDS, bacterial infectious diseases, such as Bacilluscereus, Vibrio parahaemolyticus, Enterohemorrhagic Escherichia coli,Staphylococcus aureus, MRSA, Salmonella, Botulinus, Candida, Paget'sdisease, achondroplasia, osteochodrytis, hyperparathyroidism,osteogenesis imperfecta, partial liver resection, acute liver necrosis,necrosis caused by toxin, necrosis caused by viral hepatitis, necrosiscaused by shock, necrosis caused by anoxia, B-virus hepatitis,non-A/non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholiccirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis(NASH), acetaminophen toxicity, hepatotoxicity, hepatic failure,fulminant hepatic failure, late-onset hepatic failure,“acute-on-chronic” liver failure, chronic kidney diseases, kidneydamage/injury, kidney damage/injury caused by nephritis, kidneydamage/injury caused by renal transplant, kidney damage/injury caused bysurgery, kidney damage/injury caused by administration of nephrotoxicdrugs, augmentation of chemotherapeutic effect, cytomegalovirusinfection, HCMV infection, AIDS, cancer, senile dementia, trauma,chronic bacterial infection, diseases caused by environmental pollution,aging, hypobaropathy, disease caused by histamine or leukotriene-C4release, muscular dystrophy, pyoderma and Sezary's syndrome, Addison'sdisease, pseudomembranous colitis, colitis caused by drug or radiation,ischemic acute renal insufficiency, chronic renal insufficiency,toxinosis caused by lung-oxygen or drugs, congenital hypophosphatasia,fibromatous lesions, fibrous dysplasia, bone turnover, osteolytic bonedisease, treating post-traumatic bone surgery, treating post-prostheticjoint surgery, treating post-plastic bone surgery, treating post-dentalsurgery, bone chemotherapy treatment or bone radiotherapy treatment,bone cancer, fragile plaque, disorder, occlusive disorder, stenosis,coronary artery disorders, peripheral arterial disorders, arterialocclusion, aneurysm formation, post-traumatic aneurysm formation,restenosis, post-operative graft occlusion, Guillain-Barre syndrome,Meniere's disease, polyneuritis, multiple neuritis, mononeuritis,radiculopathy, hyperthyroidism, Basedow's disease, autoimmune idiopathicthrombocytopenic purpura (autoimmune ITP), membranous nephritis,autoimmune thyroiditis, Hashimoto's thyroiditis, myasthenia gravis, coldand warm agglutinin diseases, Evan's syndrome, hemolytic uremicsyndrome/thrombotic thrombocytopenic purpura (HUS/TTP), autoimmunehemolytic anemia, agranulocytosis, pernicious anemia, megaloblasticanemia, anerythroplasia, or a combination thereof.
 42. The method ofclaim 37, wherein the disease is atopic dermatitis, rheumatoidarthritis, or ankylosing spondylitis.
 43. The method of claim 37,wherein the disease is myelodysplastic syndrome.